Heterocyclic compounds and medical use thereof

ABSTRACT

The present invention relates to heterocyclic nitrogen compounds, use thereof as a medicament and pharmaceutical compositions thereof. Furthermore, the invention provides combinations of compounds of general formula (I) with therapeutic agents, such as correctors, potentiators and amplifiers of dysfunctional proteins.

FIELD OF THE INVENTION

The present invention relates to heterocyclic nitrogen compounds, usethereof as a medicament and pharmaceutical compositions thereof.Furthermore, the invention provides combinations of compounds of generalformula (I) with therapeutic agents, such as correctors, potentiators,and amplifiers of dysfunctional proteins.

BACKGROUND OF THE INVENTION

Cystic fibrosis (CF), one of the most frequent genetic diseases, iscaused by mutations in the Cystic Fibrosis Transmembrane ConductanceRegulator (CFTR) protein (Elborn J S. Lancet 2016, 388, 2519-2531). CFTR(Accession number NCBI: NP_000483; version: NP_000483.3), a member ofthe ABC-transporter protein family, is a channel permeable to chlorideand other anions expressed in the apical membrane of epithelial cells ofthe respiratory, gastrointestinal and reproductive tract. In CF,mutations in the CFTR gene impair protein function. The result is thealteration of chloride and bicarbonate secretion with production andstagnation of a very dense mucus, resulting in damage to various organs,mainly lungs and pancreas. In the lungs, the problem is mostly theappearance and progressive persistence of respiratory infections,leading to irreversible damage to the airways caused by said infectionsand the consequent inflammation. In addition to respiratory dysfunction,mutations in the CFTR gene have an impact on other organs such aspancreas, intestine, biliary tract, vas deferens.

The known mutations of the CFTR gene are divided into six classes: classI comprises mutations that insert a premature stop codon (prematuretermination codon, PTC) resulting in production of a truncated protein,e.g. W1281X, R553X, G542X. Class II comprises missense mutations anddeletions leading to altered folding of the protein, with consequentaltered positioning on the cell surface, e.g. F508del, N1303K; class IIIcomprises missense mutations leading to defective channel opening, knownas gating mutations, e.g. G551D, G551S, G1349D; class IV comprisesmissense mutations leading to changes in the structure of the channel,which forms a distort pore with consequent defective movement of theions, known as a conductance defect, e.g. R117H, R334W, R347P. Class Vcomprises missense mutations that cause RNA splicing alterations withproduction of aberrant mRNA molecules and therefore defect of synthesisof a functional CFTR protein, e.g. 2789+5G>A, 3849+10 kb C>T. Class VIcomprises different types of mutations that increase protein turnover atthe cell surface: although the protein is expressed, it is unstablehence it is removed and degraded (e.g. 120del123, Q1412X).

In addition to CF, mutations in the CFTR gene and/or malfunctioning ofthe chloride-permeable channel are implicated in other pathologies, e.g.congenital bilateral absence of vas deferens (CBAVD), polycystic kidneysyndrome, acute, chronic and/or recurrent pancreatitis, disseminatedbronchiectasis, asthma, allergic pulmonary aspergillosis,smoking-related lung diseases such as chronic obstructive pulmonarydisease, dry eye syndrome, Sjogren's syndrome, chronic sinusitis,cholestatic jaundice (Sloane et al. 2012, PLoS ONE 7, e39809.doi:10.1371/journal. pone.0039809; Bombieri et al. 2011, J Cyst Fibros 2011,10 Suppl 2, S86-S102; Albert et al. 2008, Clinical Respiratory Medicine,Third Ed., Mosby Inc.; Levin et al. 2005, Invest Ophthalmol Vis Sci 46,1428-1434; Froussard 2007, Pancreas 35, 94-95; Son et al. 2017, J MedChem 60, 2401-2410).

Loss-of-function of CFTR can occur in different ways depending on thetype of mutation (Elborn J S. Lancet 2016, 388, 2519-2531). For examplethe F508del mutation, which is the most frequent among CF patients,affects a critical region of the CFTR protein causing multiple problems:intrinsic instability of the NBD1 domain (nucleotide binding domain 1)and alteration of the interaction between NBD1 and another domain ofsame protein called ICL4 (Lukacs G L, Verkman A S. Trends Mol Med 2012,18, 81-91; Okiyoneda T, et al. Nat Chem Biol 2013, 9, 444-454). TheF508del-CFTR protein is therefore recognized as defective by cellularquality control systems and degraded early.

The defect caused by F508del can be partially counteracted by moleculescalled “correctors” such as the compound VX-809, developed by VertexPharmaceuticals.

The effect of VX-809 (also known as lumacaftor) on CFTR function can beincreased through co-treatment with a potentiator compound such asVX-770 (ivacaftor) which stimulates the CFTR channel activity.

However, the combined treatment VX-770-VX-809 (a drug known as Orkambi)does not produce a marked effect in CF patients (Wainwright C E, et al.N Engl J Med 2015, 373, 220-231). This is due to the fact that VX-809only partially corrects the stability and maturation defect caused byF508del (Okiyoneda T, et al. Nat Chem Biol 2013, 9, 444-454). Inparticular, it is considered that VX-809 acts on the interaction defectbetween NBD1 and ICL4, but not on the instability of NBD1. Therefore,only the combination of VX-809 (or similar compound) with a second typeof corrector provided with a complementary mechanism can generate asignificant effect from a therapeutic point of view. In this respect, atriple combination including the potentiator VX-770, VX-661 (a correctoracting similarly to VX-809), and VX-445 (a new type of corrector,commercial name Elexacaftor) has recently shown efficacy on patientswith a single or double F508del mutation (Keating D, et al. N Engl J Med2018, 379, 1612-1620).

Combinational pharmacotherapy is an already established concept for thecorrection of the basic defect in CF (Veit G, et al. Mol Biol Cell 2016,27, 424-433). Treatment with combinations of compounds that act atdifferent levels on the stability, maturation and function of the CFTRprotein can have a synergistic effect on the end-result, i.e. theCFTR-mediated secretion of chloride and bicarbonate.

There is evidence that some CFTR pharmacological correctors areeffective in vitro on other proteins with congenital defects of foldingand stability (Sampson H M, et al. Orphanet J Rare Dis. 2013, 8, 11),hence said compounds are useful in correcting diseases due to defects inprotein folding, degradation, and/or maturation where the mutant proteinis recognized by the quality control systems, retained in theendoplasmic reticulum (ER), and degraded by the proteasome. For example,class 4 and 5 correctors (corr-4a, corr-4c, corr-4d, corr-5a, corr-5c)described below (Pedemonte N, et al. J Clin Invest. 2005, 115,2564-2571) have proved to be active on mutated forms of thealpha-sarcoglycan protein that cause muscular dystrophy of the cinguli(Carotti M, et al. Hum Mol Genet. 2018, 27, 969-984). In addition toVX-809 and VX-770, there are several compounds that act as correctorsand potentiators of the mutated CFTR protein (Galietta L J. PaediatrDrugs 2013, 15, 393-402).

These include furocoumarins, tricyclic aromatic compounds of natural orsynthetic origin that have various types of biological activity: uponphotoactivation with light of a suitable wavelength, they can covalentlybind the pyrimidine DNA bases and find application in the treatment ofhyperproliferative and/or autoimmune dermatological disorders, such aspsoriasis, vitiligo, or lymphomas (Dall'Acqua F, et al. CRC Handbook ofOrganic Photochemistry and Photobiology (2004) WM Hoorspool, F. Lenci,and CRC Press). Some furocoumarin derivatives, have been characterizedas potentiators of the mutated CFTR protein and as anti-inflammatoryagents (Devor D C, et al. Am J Physiol 1997, 272, C976-C988). Inparticular, 5-methoxypsoralene (5-MOP) and analogues thereof have shownthe ability to inhibit the production of IL-8 induced by Pseudomonasaeruginosa (Nicolis E, et al., Int Immunopharmacol 2009, 9, 1411-1422).Among the angular isomers, the 4,6,4′-trimethylangelicin (TMA) emergedin different cell lines both as potent NF-cB inhibitor, and potentiatorand corrector of CFTR (Tamanini A, et al. Am J Physiol 2011, 300,L380-L390; Favia M, et al. Am J Physiol 2014, 307, L48-L61).

Further tricyclic compounds with photosensitizing properties andantiproliferative activity are described in Spanò V, et al. Eur J MedChem 2017, 128, 300-318, which describespyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridines.

Patent application WO 2011/013159 describes pyrrolo[3,2-h]quinolinecompounds as photochemotherapeutic agents useful in the treatment ofneoplastic diseases.

Despite the promising results obtained with triple combinations ofcompounds, there is a significant fraction of patients carrying theF508del mutation that do not respond well to the treatment (Keating D,et al. N Engl J Med 2018, 379, 1612-1620; Heijerman H G M, et al. Lancet2019, pii: S0140-6736(19)32597-8). Furthermore, there is a need forcompounds and combinations of compounds to treat patients carrying lesscommon mutations that do not respond well to currently availabletherapies. Therefore, there is still need for additional pharmacologicalagents acting as correctors. These molecules may also be useful forother diseases involving ABC-transporters, other diseases (particularlyother chronic respiratory diseases) involving altered CFTR function, anddiseases involving misfolding, instability, and mistrafficking of mutantproteins.

SUMMARY OF THE INVENTION

The present invention is based on the finding that nitrogenatedheterocyclic compounds of formula I as described below can act ascorrectors of members of the ABC-transporter protein family, such asCFTR. The compounds of the invention can advantageously rescue thefunction of malfunctioning members of the ABC-transporter proteinfamily, such as F508del-CFTR. In particular, these compounds produce aremarkable synergistic effect if combined with other compounds such asthe known corrector VX-809. Advantageously, compounds of the inventioncan improve efficacy of read-through agents for Class I mutations likethe G542X mutation (eg mutations with a premature stop codon in the CFTRgene) by stabilizing the full length CFTR protein. Moreover, thecompounds of the invention can improve maturation and trafficking to theplasma membrane of members of the ABC-transporter protein family,especially when combined with known correctors. Further, compounds ofthe invention can advantageously rescue the function of malfunctioningintracellular proteins due to defects in protein folding, degradation,and/or maturation.

The compounds of the invention have therefore a very promisingtherapeutic potential on patients suffering from a disease associatedwith a defect in an ABC-transporter and/or a disease caused by and/orinvolving a defect in protein folding, degradation, and/or maturation,preferably said defect is caused by a genetic mutation. Preferably thecompounds of the invention can treat patients having CF, preferablyhaving CF with one or more copies of the mutation F508del whichcompromise stability and maturation of the CFTR protein.

Compounds of the present invention can further be used for the treatmentof CF patients with mutations belonging to other classes that act withmechanisms that do not involve a maturation defect. Indeed, an increasein biosynthesis and CFTR membrane transport would provide more substratefor other therapeutic agents, such as potentiator agents. A particularexample of another possible application relates to class I mutations. Inthese cases, treatment with the so-called “read-through agents” (RTA) isrequired, which favour the by-passing of the premature stop codonallowing complete synthesis of the CFTR protein. The mechanism of actionof such agents, however, implies the insertion of a random amino acid atthe mutated codon and therefore the possible production of a partiallydefective protein. The compounds of the present invention thereforeincrease the efficacy of the RTAs by improving the stability andmaturation of the protein produced.

The most promising derivatives in terms of biological activity belong toheterocyclic systems with a general 1 and 2 pyrrolo[3,2-h]quinolinestructure, known for their marked abilities as drugs useful inneoplastic pathologies upon photoactivation (WO 2011/013159; Spanò V, etal. Eur J Med Chem. 2017, 128, 300-318).

An object of the present invention therefore comprises theidentification of further compounds, capable of correcting the basicdefect of a ABC-transporter family protein, e.g. CFTR, in particularF508del-CFTR, as demonstrated by functional assays carried out both oncells having the expression of the mutated protein, and directly onprimary epithelial cells obtained from patients with the mutationF508del.

The compounds object of the present invention show high efficacy incombination with further therapeutic agents, e.g. already knowncorrector agents, such as the compound VX-809. This result is ofconsiderable importance as the clinical efficacy of first-generationcorrectors such as VX-809 (lumacaftor) and VX-661 (tezacaftor) islimited and it is therefore commonly believed that the treatment ofpatients with combinations of correctors having complementary mechanismsis necessary (Lukacs G L, et al. Trends Mol Med. 2012, 18, 81-91;Okiyoneda T, et al. Nat Chem Biol. 2013, 9, 444-454).

An object of the present invention is therefore a compound of generalformula (I):

wherein:A is a pentatomic or hexatomic aromatic heterocyclic ring, comprisingone, two or three heteroatoms selected from nitrogen, oxygen and sulfur;R is selected from the group consisting of: hydrogen, linear or branchedC1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, arylsulfonyl, halogen and alkylamine, wherein saidlinear or branched C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, arylsulfonyl or alkylamine is optionallysubstituted with one or more substituents independently selected from:linear or branched C1-C6 alkyl, nitro, amino, halogen, haloalkyl andalkoxy;R¹ and R² are independently selected from the group consisting of:hydrogen, carboxylic acid, carboxylic ester, carboxamide from primary,secondary or tertiary amine, halogen, nitro, amine, azide, alkylamine,arylalkyl and trifluoroalkyl, wherein said carboxylic acid, carboxylicester, carboxamide from primary, secondary or tertiary amine, halogen,nitro, amine, azide, alkylamine or trifluorolalkyl is optionallysubstituted with one or more substituents independently selected from:linear or branched C1-C6 alkyl, cycloalkyl, nitro, amino, halogen,arylsulfonyl, optionally substituted heteroaryl and haloalkyl;R³ is absent or present and is selected from the group consisting of:carbonitrile, carboxylic ester, carboxamide, alkylsulfonyl,arylsulfonyl, wherein said carboxylic ester, carboxamide, alkylsulfonylor arylsulfonyl is optionally substituted with one or more substituentsindependently selected from: linear or branched C1-C6 alkyl, nitro,amino, halogen and haloalkyl;B is a cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring, whereinsaid heterocycloalkyl or heteroaryl ring comprises at least oneheteroatom selected from nitrogen, oxygen and sulfur;R⁴ is selected from the group consisting of: hydrogen, alkyl, aryl,arylalkyl and heteroaryl;X is selected from the group consisting of: C═O, C—O-alkyl, andC—NR^(a)R^(b);R^(a) and R^(b) are independently selected from the group consisting of:hydrogen, alkyl, cycloalkane, aryl, arylalkyl, heteroaryl,heteroarylalkyl, acetyl, arylsulfonyl; wherein said alkyl, cycloalkane,aryl, arylalkyl, heteroaryl, heteroarylalkyl, acetyl or arylsulfonyl isoptionally substituted with one or more substituents independentlyselected from: C1-C6 alkyl, nitro, amino, halogen and haloalkyl;Y is absent or present and is selected from the group consisting of:hydrogen, alkyl, aryl and alkylamine; wherein when X is C—O-alkyl orC—NR^(a)R^(b), Y is absent;Q is a carbon or nitrogen atom, wherein when Q is a nitrogen atom, R3 isabsent;n is 0, 1, 2 or 3;m is 1 or 2;or a pharmaceutically acceptable salt, tautomer, stereoisomer,deuterated derivative, active metabolite thereof for use in thetreatment and/or prevention of a pathology associated with a defect inan ABC (ATP-binding cassette) transporter and/or for use in thetreatment and/or prevention of a pathology associated with at least oneof the following: protein mutation, protein misfolding, proteindegradation, protein maturation, protein trafficking.

In a preferred embodiment, the present invention provides a compound ofgeneral formula (I):

wherein:A is a pentatomic or hexatomic aromatic heterocyclic ring, comprisingone, two or three heteroatoms selected from nitrogen, oxygen and sulfur;R is selected from the group consisting of: hydrogen, linear or branchedC1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,arylsulfonyl and alkylamine, wherein said linear or branched C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,arylsulfonyl or alkylamine is optionally substituted with one or moresubstituents independently selected from: linear or branched C1-C6alkyl, nitro, amino, halogen, haloalkyl and alkoxy;R¹ and R² are independently selected from the group consisting of:hydrogen, carboxylic acid, carboxylic ester, carboxamide from primary,secondary or tertiary amine, halogen, nitro, amine, azide, alkylamineand trifluoroalkyl, wherein said carboxylic acid, carboxylic ester,carboxamide from primary, secondary or tertiary amine, halogen, nitro,amine, azide, alkylamine or trifluorolalkyl is optionally substitutedwith one or more substituents independently selected from: linear orbranched C1-C6 alkyl, nitro, amino, halogen and haloalkyl;R³ is selected from the group consisting of: carbonitrile, carboxylicester, carboxamide, alkylsulfonyl, arylsulfonyl, wherein said carboxylicester, carboxamide, alkylsulfonyl or arylsulfonyl is optionallysubstituted with one or more substituents independently selectedselected from: linear or branched C1-C6 alkyl, nitro, amino, halogen andhaloalkyl;B is an aromatic or non-aromatic cycloalkyl, aryl, heterocycloalkyl orheteroaryl ring, wherein said heterocycloalkyl or heteroaryl ringcomprises at least one heteroatom selected from nitrogen, oxygen andsulfur;R⁴ is selected from the group consisting of: hydrogen, alkyl, aryl,arylalkyl and heteroaryl;X is selected from the group consisting of: C═O, C—O-alkyl andC—NR^(a)R^(b);R^(a) and R^(b) are independently selected from the group consisting of:hydrogen, alkyl, cycloalkane, aryl, arylalkyl, heteroaryl,heteroarylalkyl, acetyl; wherein said alkyl, cycloalkane, aryl,arylalkyl, heteroaryl, heteroarylalkyl or acetyl is optionallysubstituted with one or more substituents independently selected from:C1-C6 alkyl, nitro, amino, halogen and haloalkyl;Y is absent or present and is selected from the group consisting of:hydrogen, alkyl, aryl and alkylamine; wherein when X is C—O-alkyl orC—NR^(a)R^(b), Y is absent;Q is a carbon or nitrogen atom; wherein when Q is a nitrogen atom, X isnot C—O-alkyl o C—NR^(a)R^(b) and Y is absent;n is 0, 1, 2 or 3;m is 1 or 2;or a pharmaceutically acceptable salt, tautomer, stereoisomer,deuterated derivative, active metabolite thereof for use in thetreatment and/or prevention of a pathology associated with a defect inan ABC (ATP-binding cassette) transporter.

Preferred compounds of the present invention include:

Also preferably, compounds of the present invention include:

A further object of the present invention is a pharmaceuticalcomposition comprising the compound as defined above and apharmaceutically acceptable carrier for use in the treatment and/orprevention of a pathology associated with a defect in an ABC(ATP-binding cassette) transporter and/or for use in the treatmentand/or prevention of a pathology associated with at least one of thefollowing: protein mutation, protein misfolding, protein degradation,protein maturation, protein trafficking.

Preferably, said ABC (ATP-binding cassette) transporter is CFTR (CysticFibrosis Transmembrane Conductance Regulator).

Preferably, said pathology is selected from the group consisting of:cystic fibrosis, Limb-Girdle muscular dystrophy (LGMD), CongenitalBilateral Absence of Vas Deferens (CBAVD), acute, chronic, recurrentand/or autoimmune pancreatitis, disseminated bronchiectasis, asthma,allergic pulmonary aspergillosis, smoking-related lung pathology, dryeye syndrome, Sjogren's syndrome, chronic sinusitis, cholestaticjaundice, emphysema, idiopathic chronic pancreatitis, isolatedobstructive azoospermia, sclerosing cholangitis, panbronchiolite,neonatal hypertripsinemia, adrenoleukodystrophy, Stargardt disease,Tangier disease, progressive familial intrahepatic cholestasis,Dubin-Johnson syndrome, elastic pseudoxantoma, persistenthyperinsulinemic hypoglycemia of infancy due to focal adenomatoushyperplasia, senile macular degeneration, retinitis pigmentosa and“cone-rod” retinal dystrophy. Still preferably, said smoking-relatedlung disease is chronic obstructive pulmonary disease.

More preferably, said pathology is cystic fibrosis.

Still preferably, the CFTR (Cystic Fibrosis Transmembrane conductanceRegulator) protein bears the F508del mutation and/or the G542X prematurestop codon mutation. More preferably, said pathology is caused by amutation in the CFTR gene, in particular the F508del mutation and/or theG542X premature stop codon mutation.

In a preferred embodiment, the present invention provides a combinationof a compound of general formula (I) or a pharmaceutically acceptablesalt, tautomer, stereoisomer, deuterated derivative, active metabolitethereof as defined above and at least one further therapeutic agent.

Preferably, said further therapeutic agent is useful for use in thetreatment and/or prevention of a pathology associated with a defect inan ABC (ATP-binding cassette) transporter and/or for use in thetreatment and/or prevention of a pathology associated with at least oneof the following: protein mutation, protein misfolding, proteindegradation, protein maturation, protein trafficking.

Still preferably, said further therapeutic agent is selected from thegroup consisting of: a corrector, a potentiator, an amplifier, an agentthat increases the read-through of the stop codons, a furocoumarin, anantibiotic or anti-infective, an anti-inflammatory agent, a mucolyticand a bronchodilator.

Preferably, said corrector is selected from: VX809(3-(6-(1-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid, lumacaftor), VX770 (ivacaftor), VX770-VX809 (orkambi), VX661(tezacaftor), VX445, VX659, VX983, VX152, VX440, ABBV-2737, GLPG2222,GLPG2851, GLPG2665, GLPG2737, GLPG3221, PTI-801, FDL169,bisaminomethylthiazole (corr-4a), W1282Xcorr-B09, W1282Xcorr-A23 and afurocoumarin.

Preferably, said potentiator is selected from: VX770 (ivacaftor), VX561,GLPG1837, GLPG2545, GLPG3067, genistein, phenylglycine (PG-01), PTI-808,1,4-dihydropyridine, tetrahydrobenzothiophene, benzofuran, anthraquinoneand sulphonamide.

Preferably, said amplifier is PTI-428.

Preferably, said agent that increases the “read-through” of the stopcodons is Ataluren (PTC124)(3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid).

Preferably, said furocoumarin is selected from: 5-methoxypsoralene(5-MOP), 4,6,4′-trimethylangelicin (TMA), 8-methoxypsoralene (8-MOP),Angelicin and a pyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridine.

Preferably, said antibiotic or anti-infective is selected from:penicillins, preferably amoxicillin, clavulanic acid, cloxacillin,dicloxacillin, ticarcillin; cephalosporins, preferably cephalexin,cefdinir, cefprozil, cefaclor, cefuroxime; sulfamethoxazole,trimethoprim, erythromycin, sulfisoxazole, macrolides, preferablyerythromycin, clarithromycin, azithromycin; tetracyclines, preferablytetracycline, doxycycline, minocycline, and tigecycline; vancomycin;imipenem; meropenem; colistimethate; aminoglycosides, preferablytobramycin, amikacin, gentamicin; quinolones, preferably ciprofloxacinor levofloxacin; aztreonam; linezolid upon oral, inhalation,intravenous, intra-muscular administration.

Preferably, said anti-inflammatory is selected from: corticosteroids,preferably by inhalation or oral route, preferably Budesonide or Clenil,and non-steroidal drugs, preferably ibuprofen. Preferably, saidmucolytic is selected from: dornase alfa (Pulmozyme), N-acetylcysteine(Fluimucil), saline hypertonic, mannitol (Bronchitol).

Preferably, said bronchodilator is selected from: salbutamol, albuteroland levalbuterol.

Preferably, the combination comprises as the at least one furthertherapeutic agent: one corrector, one potentiator, two correctors andone potentiator, or one corrector and one potentiator. More preferably,the combination comprises as the at least one further therapeutic agent:

-   -   VX-809, VX770, VX661 or VX445, or    -   VX770, VX661 and VX445, or    -   genistein and VX809.

In a preferred embodiment, the present invention provides apharmaceutical composition comprising the combination as defined aboveand a pharmaceutically acceptable carrier.

In a further preferred embodiment, the present invention provides thecombination as defined above for use as a medicament.

A further object of the present invention is the combination as definedabove or the pharmaceutical composition as defined above for use in thetreatment and/or prevention of a pathology associated with a defect inan ABC (ATP-binding cassette) transporter and/or for use in thetreatment and/or prevention of a pathology associated with at least oneof the following: protein mutation, protein misfolding, proteindegradation, protein maturation, protein trafficking. Preferably, saidABC transporter is CFTR (Cystic Fibrosis Transmembrane ConductanceRegulator). Preferably, said pathology is selected from the groupconsisting of: cystic fibrosis, Limb-Girdle muscular dystrophy (LGMD),Congenital Bilateral Absence of Vas Deferens (CBAVD), acute, chronic,recurrent and/or autoimmune pancreatitis, disseminated bronchiectasis,asthma, allergic pulmonary aspergillosis, smoking-related lungpathology, dry eye syndrome, Sjogren's syndrome, chronic sinusitis,cholestatic jaundice, emphysema, idiopathic chronic pancreatitis,isolated obstructive azoospermia, sclerosing cholangitis,panbronchiolite, neonatal hypertripsinemia, adrenoleukodystrophy,Stargardt disease, Tangier disease, progressive familial intrahepaticcholestasis, Dubin-Johnson syndrome, elastic pseudoxantoma, persistenthyperinsulinemic hypoglycemia of infancy due to focal adenomatoushyperplasia, senile macular degeneration, retinitis pigmentosa and“cone-rod” retinal dystrophy. Still preferably, said smoking-relatedlung disease is chronic obstructive pulmonary disease.

In a preferred embodiment, the present invention provides a compound ofgeneral formula (I):

wherein:A is a pentatomic or hexatomic aromatic heterocyclic ring, comprisingone, two or three heteroatoms selected from nitrogen, oxygen and sulfur;R is selected from the group consisting of: hydrogen, linear or branchedC1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, arylsulfonyl, halogen and alkylamine, wherein saidlinear or branched C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, arylsulfonyl or alkylamine is optionallysubstituted with one or more substituents independently selected from:linear or branched C1-C6 alkyl, nitro, amino, halogen, haloalkyl andalkoxy;R¹ and R² are independently selected from the group consisting of:hydrogen, carboxylic acid, carboxylic ester, carboxamide from primary,secondary or tertiary amine, halogen, nitro, amine, azide, alkylamine,arylalkyl and trifluoroalkyl, wherein said carboxylic acid, carboxylicester, carboxamide from primary, secondary or tertiary amine, halogen,nitro, amine, azide, alkylamine or trifluorolalkyl is optionallysubstituted with one or more substituents independently selected from:linear or branched C1-C6 alkyl, cycloalkyl, nitro, amino, halogen,arylsulfonyl, optionally substituted heteroaryl and haloalkyl;R³ is absent or present and is selected from the group consisting of:carbonitrile, carboxylic ester, carboxamide, alkylsulfonyl,arylsulfonyl, wherein said carboxylic ester, carboxamide, alkylsulfonylor arylsulfonyl is optionally substituted with one or more substituentsindependently selected from: linear or branched C1-C6 alkyl, nitro,amino, halogen and haloalkyl;B is a cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring, whereinsaid heterocycloalkyl or heteroaryl ring comprises at least oneheteroatom selected from nitrogen, oxygen and sulfur;R⁴ is selected from the group consisting of: hydrogen, alkyl, aryl,arylalkyl and heteroaryl;X is selected from the group consisting of: C═O, C—O-alkyl, andC—NR^(a)R^(b);R^(a) and R^(b) are independently selected from the group consisting of:hydrogen, alkyl, cycloalkane, aryl, arylalkyl, heteroaryl,heteroarylalkyl, acetyl, arylsulfonyl; wherein said alkyl, cycloalkane,aryl, arylalkyl, heteroaryl, heteroarylalkyl, acetyl or arylsulfonyl isoptionally substituted with one or more substituents independentlyselected from: C1-C6 alkyl, nitro, amino, halogen and haloalkyl;Y is absent or present and is selected from the group consisting of:hydrogen, alkyl, aryl and alkylamine; wherein when X is C—O-alkyl orC—NR^(a)R^(b), Y is absent;Q is a carbon or nitrogen atom, wherein when Q is a nitrogen atom, R3 isabsent;n is 0, 1, 2 or 3;m is 1 or 2;or a pharmaceutically acceptable salt, tautomer, stereoisomer,deuterated derivative, active metabolite thereof. Preferably, when X isC═O, R² is different from hydrogen.

In another preferred embodiment, the present invention provides acompound of general formula (I):

wherein:A is a pentatomic or hexatomic aromatic heterocyclic ring, comprisingone, two or three heteroatoms selected from nitrogen, oxygen and sulfur;R is selected from the group consisting of: hydrogen, linear or branchedC1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,arylsulfonyl and alkylamine, wherein said linear or branched C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,arylsulfonyl or alkylamine is optionally substituted with one or moresubstituents independently selected from: linear or branched C1-C6alkyl, nitro, amino, halogen, haloalkyl and alkoxy;R¹ and R² are independently selected from the group consisting of:hydrogen, carboxylic acid, carboxylic ester, carboxamide from primary,secondary or tertiary amine, halogen, nitro, amine, azide, alkylamineand trifluoroalkyl, wherein said carboxylic acid, carboxylic ester,carboxamide from primary, secondary or tertiary amine, halogen, nitro,amine, azide, alkylamine or trifluorolalkyl is optionally substitutedwith one or more substituents independently selected from: linear orbranched C1-C6 alkyl, nitro, amino, halogen and haloalkyl;R³ is selected from the group consisting of: carbonitrile, carboxylicester, carboxamide, alkylsulfonyl, arylsulfonyl, wherein said carboxylicester, carboxamide, alkylsulfonyl or arylsulfonyl is optionallysubstituted with one or more substituents independently selectedselected from: linear or branched C1-C6 alkyl, nitro, amino, halogen andhaloalkyl; B is an aromatic or non-aromatic cycloalkyl, aryl,heterocycloalkyl or heteroaryl ring, wherein said heterocycloalkyl orheteroaryl ring comprises at least one heteroatom selected fromnitrogen, oxygen and sulfur;R⁴ is selected from the group consisting of: hydrogen, alkyl, aryl,arylalkyl and heteroaryl;X is selected from the group consisting of: C═O, C—O-alkyl andC—NR^(a)R^(b);R^(a) and R^(b) are independently selected from the group consisting of:hydrogen, alkyl, cycloalkane, aryl, arylalkyl, heteroaryl,heteroarylalkyl, acetyl; wherein said alkyl, cycloalkane, aryl,arylalkyl, heteroaryl, heteroarylalkyl or acetyl is optionallysubstituted with one or more substituents independently selected from:C1-C6 alkyl, nitro, amino, halogen and haloalkyl;Y is absent or present and is selected from the group consisting of:hydrogen, alkyl, aryl and alkylamine; wherein when X is C—O-alkyl orC—NR^(a)R^(b), Y is absent;Q is a carbon or nitrogen atom; wherein when Q is a nitrogen atom, X isnot C—O-alkyl o C—NR^(a)R^(b) and Y is absent;n is 0, 1, 2 or 3;m is 1 or 2;or a pharmaceutically acceptable salt, tautomer, stereoisomer,deuterated derivative, active metabolite thereof, preferably whereinwhen X is C═O, R² is different from hydrogen.

Preferred compounds according to the latter two embodiments are:

-   Ethyl    1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP015);-   Ethyl    1-(3-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP016);-   Ethyl    1-(4-chlorobenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP017);-   Ethyl    7-[(4-chlorophenyl)sulfonyl]-1-(4-methylbenzyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP018);-   Ethyl    7-(benzenesulfonyl)-1-[(2,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP021);-   Ethyl    7-(benzenesulfonyl)-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP025);-   Propan-2-yl    7-(benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP022);-   Ethyl    7-(4-methylbenzene-1-sulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP023);-   Ethyl    7-(metansulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP024);-   Methyl    1-(4-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP019);-   Methyl    1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP020);-   Ethyl    8-(benzenesulfonyl)-1-[(4-methylphenyl)methyl]-9-oxo-1,4,5,6,9,10-hexahydropyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridine-2-carboxylate    (PP048);-   Ethyl    7-(benzenesulfonyl)-1-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP060);-   Ethyl    7-(benzenesulfonyl)-1-[(4-iodophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP062);-   Ethyl    7-(benzenesulfonyl)-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP064);-   Ethyl    7-(benzenesulfonyl)-1-[(6-methylpyridin-3-yl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP066);-   Ethyl    7-(benzenesulfonyl)-8-oxo-1-[(2,4,6-trimethylphenyl)methyl]-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP068);-   Ethyl    7-(benzenesulfonyl)-8-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP070);-   Ethyl    7-(benzenesulfonyl)-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP072);-   Ethyl    7-(benzenesulfonyl)-1-[3-(dimethylamino)propyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP074);-   Propan-2-yl    7-(benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP103);-   Propan-2-yl    7-(benzenesulfonyl)-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP105);-   Propan-2-yl    7-(benzenesulfonyl)-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP107);-   7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP083);-   7-(Benzenesulfonyl)-N-cyclopropyl-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP084);-   7-(Benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP085);-   7-(Benzenesulfonyl)-N-cyclopropyl-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP087);-   7-(Benzenesulfonyl)-1-[(4-bromophenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP096);-   7-(Benzenesulfonyl)-1-[(4-bromophenyl)methyl]-N-cyclopropyl-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP098);-   Ethyl    7-(benzenesulfonyl)-3-chloro-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP076);-   Ethyl    7-(benzenesulfonyl)-3-iodo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP077);    ) allowing the isolation of N-methyl derivatives and O-methyl    derivatives as pure products.-   Ethyl    7-(benzenesulfonyl)-8-methoxy-1-[(4-methylphenyl)methyl]-4,5-dihydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP014);-   Ethyl    8-(benzenesulfonyl)-9-methoxy-1-[(4-methylphenyl)methyl]-1,4,5,6-tetrahydropyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridine-2-carboxylate    (PP055);-   Ethyl    7-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP008);-   Ethyl    8-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-9-oxo-1,4,5,6,9,10-hexahydropyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridine-2-carboxylate    (PP056);-   Ethyl 3-bromo    1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP027);-   Ethyl 3-bromo    1-(3-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP028);-   Ethyl 3-bromo    1-(4-chlorobenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP029);-   Methyl    3-bromo-1-(4-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP031);-   Methyl    3-bromo-1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP032);-   Ethyl    3-bromo-7-[(4-chlorophenyl)sulfonyl]-1-(3-methylbenzyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP030);-   Ethyl    7-(benzenesulfonyl)-3-bromo-1-[(2,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP033);-   Ethyl    7-(benzenesulfonyl)-3-bromo-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP037);-   Propan-2-yl    7-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP034);-   Ethyl    3-bromo-7-(4-methylbenzene-1-sulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP035);-   Ethyl    3-bromo-7-(metansulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP036);-   Ethyl    7-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-8,9-dihydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (14, PP057);-   Ethyl    7-(benzenesulfonyl)-3-bromo-1-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP061);-   Ethyl    7-(benzenesulfonyl)-3-bromo-1-[(4-iodophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP063);-   Ethyl    7-(benzenesulfonyl)-3-bromo-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP065);-   Ethyl    7-(benzenesulfonyl)-3-bromo-1-[(6-methylpyridin-3-yl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP067);-   Ethyl    7-(benzenesulfonyl)-3-bromo-8-oxo-1-[(2,4,6-trimethylphenyl)methyl]-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP069);-   Ethyl    7-(benzenesulfonyl)-3-bromo-8-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP071);-   Ethyl    7-(benzenesulfonyl)-3-bromo-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP073);-   Ethyl    7-(benzenesulfonyl)-1-[3-(dimethylamino)propyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP075);-   Propan-2-yl    7-(benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP104);-   Propan-2-yl    7-(benzenesulfonyl)-3-bromo-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP106);-   Propan-2-yl    7-(benzenesulfonyl)-3-bromo-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (PP108);-   7-(Benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP091);-   7-(Benzenesulfonyl)-N-cyclopropyl-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP092);-   7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP086);-   7-(Benzenesulfonyl)-3-bromo-N-cyclopropyl-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP088);-   7-(Benzenesulfonyl)-3-bromo-1-[(4-bromophenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP097);-   7-(Benzenesulfonyl)-3-bromo-1-[(4-bromophenyl)methyl]-N-cyclopropyl-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP099);-   7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylic    acid (PP090);-   7-(Benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylic    acid (PP081);-   7-(Benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylic    acid (PP078);-   7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylic    acid (PP079);-   7-(Benzenesulfonyl)-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylic    acid (PP094);-   7-(Benzenesulfonyl)-3-bromo-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylic    acid (PP095);-   7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP093);-   7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP082);-   7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP080);-   7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP089);-   N,7-di(benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP100);-   7-(Benzenesulfonyl)-3-bromo-N-tert-butyl-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP101);-   7-(Benzenesulfonyl)-3-bromo-N-(5-tert-butyl-1,2-oxazol-3-yl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide    (PP102);-   Ethyl    1-(4-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-8,9-dihydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate    (13, PP058);-   Ethyl    2-amino-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ1);-   Ethyl    2-amino-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ3);-   Ethyl    2-amino-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ5);-   Ethyl    2-amino-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ7);-   Ethyl    2-[(benzenesulfonyl)amino]-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ9);-   Ethyl    2-[(benzenesulfonyl)amino]-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ11);-   Ethyl    2-[(benzenesulfonyl)amino]-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ13);-   Ethyl    2-[(benzenesulfonyl)amino]-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ15);-   Ethyl    2-amino-7-bromo-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ2);-   Ethyl    2-amino-7-bromo-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ4);-   Ethyl    2-amino-7-bromo-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ6);-   Ethyl    2-amino-7-bromo-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ8);-   Ethyl    2-[(benzenesulfonyl)amino]-7-bromo-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ10);-   Ethyl    2-[(benzenesulfonyl)amino]-7-bromo-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ12);-   Ethyl    2-[(benzenesulfonyl)amino]-7-bromo-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ14);-   Ethyl    2-[(benzenesulfonyl)amino]-7-bromo-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate    (SVQ16);-   Ethyl    3-(benzenesulfonyl)-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate    (QZN1);-   Ethyl    3-(benzenesulfonyl)-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZN5);-   Propan-2-yl    3-(benzenesulfonyl)-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate    (QZN9);-   Propan-2-yl    3-(benzenesulfonyl)-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZN13);-   Ethyl    3-(benzenesulfonyl)-2-methoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate    (QZN3);-   Ethyl    3-(benzenesulfonyl)-1-methyl-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate    (QZN4);-   Ethyl    3-(benzenesulfonyl)-2-methoxy-6,7-dihydro-5H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZN7);-   Ethyl    3-(benzenesulfonyl)-1-methyl-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZN8);-   Propan-2-yl    3-(benzenesulfonyl)-2-methoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate    (QZN11);-   Propan-2-yl    3-(benzenesulfonyl)-1-methyl-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate    (QZN12);-   Propan-2-yl    3-(benzenesulfonyl)-2-methoxy-6,7-dihydro-5H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZN15);-   Propan-2-yl    3-(benzenesulfonyl)-1-methyl-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZN16);-   Ethyl    3-(benzenesulfonyl)-9-bromo-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate    (QZN2);-   Ethyl    3-(benzenesulfonyl)-10-bromo-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZN6);-   Propan-2-yl    3-(benzenesulfonyl)-9-bromo-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate    (QZN10);-   Propan-2-yl    3-(benzenesulfonyl)-10-bromo-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZN14);-   Ethyl 2-amino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate    (QZQ1);-   Ethyl    2-amino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZQ5);-   Propan-2-yl    2-amino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate (QZQ17);-   Propan-2-yl    2-amino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZQ21);-   Ethyl 2-anilino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate    (QZQ2);-   Ethyl    2-(cyclohexylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate    (QZQ3);-   Ethyl    2-anilino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZQ6);-   Ethyl    2-(cyclohexylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZQ7);-   Propan-2-yl    2-anilino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate    (QZQ18);-   Propan-2-yl    2-(cyclohexylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate    (QZQ19);-   Propan-2-yl    2-anilino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZQ22);-   Propan-2-yl    2-(cyclohexylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZQ23);-   Ethyl    2-(cyclopentylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate    (QZQ14);-   Ethyl    2-(cyclopentylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZQ15);-   Propan-2-yl    2-(cyclopentylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate    (QZQ20);-   Propan-2-yl    2-(cyclopentylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZQ24);-   Ethyl 2-acetamido-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate    (QZQ4);-   Ethyl    2-acetamido-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZQ8);-   Propan-2-yl    2-acetamido-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate    (QZQ25);-   Propan-2-yl    2-acetamido-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate    (QZQ26);-   Ethyl    7-(benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate    (PZ1);-   Ethyl    7-(benzenesulfonyl)-2-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate    (PZ2);-   Ethyl    7-(benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate    (PZ3);-   Ethyl    7-(benzenesulfonyl)-2-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate    (PZ4);-   Ethyl    7-(benzenesulfonyl)-1-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate    (PZ5);-   Ethyl    7-(benzenesulfonyl)-2-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate    (PZ6);-   Ethyl    7-(benzenesulfonyl)-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate    (PZ7);-   Ethyl    7-(benzenesulfonyl)-2-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate    (PZ8).

Further objects of the invention are:

-   -   a pharmaceutical composition comprising the compound as defined        in the two latter preferred embodiments and a pharmaceutically        acceptable carrier;    -   a compound as defined in the two latter preferred embodiments        for use as a medicament. Preferably, the invention provides said        compound or pharmaceutical composition for use in the treatment        and/or prevention of a pathology associated with a defect in an        ABC (ATP-binding cassette) transporter and/or for use in the        treatment and/or prevention of a pathology associated with at        least one of the following: protein mutation, protein        misfolding, protein degradation, protein maturation, protein        trafficking. Preferably, said ABC transporter is CFTR (Cystic        Fibrosis Transmembrane Conductance Regulator). Preferably, said        pathology is selected from the group consisting of: cystic        fibrosis, Limb-Girdle muscular dystrophy (LGMD), Congenital        Bilateral Absence of Vas Deferens (CBAVD), acute, chronic,        recurrent and/or autoimmune pancreatitis, disseminated        bronchiectasis, asthma, allergic pulmonary aspergillosis,        smoking-related lung pathology, dry eye syndrome, Sjogren's        syndrome, chronic sinusitis, cholestatic jaundice, emphysema,        idiopathic chronic pancreatitis, isolated obstructive        azoospermia, sclerosing cholangitis, panbronchiolite, neonatal        hypertripsinemia, adrenoleukodystrophy, Stargardt disease,        Tangier disease, progressive familial intrahepatic cholestasis,        Dubin-Johnson syndrome, elastic pseudoxantoma, persistent        hyperinsulinemic hypoglycemia of infancy due to focal        adenomatous hyperplasia, senile macular degeneration, retinitis        pigmentosa and “cone-rod” retinal dystrophy. Still preferably,        said smoking-related lung disease is chronic obstructive        pulmonary disease.

The following definitions of preferred substituents apply to allabove-defined embodiments of the present invention.

Preferably, when X is C═O, R² is different from hydrogen.

Preferably, R² is halogen, preferably bromine.

Preferably, A is a pentatomic aromatic heterocyclic ring comprising oneor two nitrogen atoms. More preferably, A is selected from the groupconsisting of:

Preferably, R is selected from the group consisting of: hydrogen, linearor branched C1-C6 alkyl, aryl, arylalkyl, heteroarylalkyl, arylsulfonyland alkylamine. Still preferably, R is a benzyl or a methylpyridinyloptionally substituted with one or more substituents independentlyselected from: linear or branched C1-C6 alkyl, haloalkyl, halogen(preferably chlorine) and alkoxy. Even more preferably, R is selectedfrom the group consisting of: SO₂Ph, hydrogen, methyl, benzyl, phenyl,methylpyridinyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, halobenzyl(preferably chlorobenzyl) and CH₂CH₂CH₂(NMe)₂.

Preferably, R¹ is hydrogen, carboxylic acid, carboxylic ester,carboxamide from primary, secondary or tertiary amine or halogen. Stillpreferably, R¹ is hydrogen, COOEt, COOMe, COOiPr, COOtBu, COOH, CONH₂,CONHiPr, CONHcyclopropyl, CONHSO₂Ph, CONHtBu, CONHtButisoxazole or Br.

Preferably, R² is hydrogen, carboxylic ester or halogen. Stillpreferably, R² is hydrogen, bromine, iodine, chlorine, COOEt, COOMe,COOiPr or COOtBu.

More preferably, R¹ and/or R² is a carboxylic ester or a carboxamidefrom primary, secondary or tertiary amine.

Preferably, R³ is carbonitrile, alkylsulfonyl or arylsulfonyl,preferably SO₂Ph, optionally substituted with one or more substituentsindependently selected from: linear or branched C1-C6 alkyl and halogen,preferably chlorine. Still preferably, R³ is SO₂Ph, 4-Cl—SO₂Ph,SO₂Ph-4-Me, SO₂Me, or CN.

Preferably, R³ is arylsulfonyl or R³ is absent, Q is a nitrogen atom, Xis C—NR^(a)R^(b), R^(a) is H and R^(b) is arylsulfonyl.

Preferably, B is a cycloalkyl or aryl ring. Still preferably, B iscyclohexyl, cycloheptyl, phenyl, or cycloheptadienyl.

Preferably, R⁴ is hydrogen.

Preferably, X is C═O, C—OMe, C—NH₂ or C—NHR^(a).

Preferably,

-   -   Q is a carbon atom, X is C═O and Y is hydrogen or alkyl, or    -   Q is a carbon atom, X is C—Oalkyl and Y is absent, or    -   Q is a nitrogen atom, X is C—NR^(a)R^(b) and Y is absent.

Preferably R^(a) and R^(b) are independently selected from the groupconsisting of: hydrogen, arylsulfonyl, acetyl, aryl and cycloalkane.More preferably, R^(a) and R^(b) are independently selected from thegroup consisting of: SO₂Ph, Ph, cyclohexyl and cyclopentyl.

Preferably, when X is C═O, Y is hydrogen or alkyl or when X isC—O-alkyl, preferably C—OMe, Y is absent. Still preferably, when X isC═O, Y is hydrogen or methyl or when X is C—O-alkyl, preferably C—OMe, Yis absent.

Preferably, Y is absent or present and is hydrogen or alkyl (e.g.methyl).

Preferably, Q is a carbon atom.

Preferably, n is 1 or 2.

Preferably, m is 1.

Preferably, the compound or the pharmaceutically acceptable salt,tautomer, stereoisomer, deuterated derivative, active metabolite thereofas defined above has one of the following general formulas:

Furthermore, the compounds of the invention are also for use in thetreatment and/or prevention of a disease caused by and/or involving amaturation defect of at least one protein, e.g. alpha-sarcoglycan.

As defined herein, a “pathology associated with a protein mutation” is adisease caused by a mutation in a gene encoding a protein. Such mutationcauses loss of function of the protein because the protein synthesis isarrested, the resulting protein is unstable and/or misfolded, or thestructure of a critical region of the protein involved in activity issignificantly altered. Said diseases are generally Mendelian diseases ordiseases due to complex genetic defects. Examples of pathologiesassociated with protein mutation are cystic fibrosis, Duchenne musculardystrophy, spinal muscular atrophy, sickle cell disease, Tay-Sachsdisease.

As defined herein, a “pathology associated with protein misfolding” is adisease in which a protein is structurally abnormal assuming atridimensional conformation significantly different from the structureof the wild type protein. When a protein fails to fold correctly, it maylose its normal function or it may become noxious to the cell as aresult of a gain of toxic function. Protein misfolding may be the resultof changes in the primary amino acid sequence of the protein (due forinstance to a gene mutation or post-translational modifications such ashyperphosphorylation), changes in temperature or pH, an increase inproduction of a protein, or a decrease in its clearance. Advancing ageis a strong risk factor, as is traumatic brain injury. Diseasesassociated to protein misfolding include but are not limited to priondiseases, Alzheimer's disease, Parkinson's disease, amyloidosis,amyotrophic lateral sclerosis, trinucleotide repeat disorders (e.g.hungtinton's disease), retinitis pigmentosa with rhodopsin mutations.

As defined herein, a “pathology associated with protein degradation” isa disease in which cell protein degradation pathways, the proteinquality control responsible for protein degradation through theubiquitin-proteasome system (UPS), recognize mutated/misfolded proteinsand degrade them. In case of diseases related to protein misfolding, aprotein may misfold but does not necessarily lose entirely itsfunctional activity. Nevertheless it is recognized as potentially toxicand degraded, thereby causing a loss of protein function of what wouldotherwise have been a partially active protein.

As defined herein, “pathology associated with a protein maturation” is adisease in which a protein, due to mutations affecting the proteinitself or other factors, is unable to undergo the modifications (e.g.glycosylation) that are required to generate the normal and mature formof the protein. The inability to mature can be due to misfolding orother types of modifications of the protein structure. Defectivematuration can result in altered subcellular localization of theprotein. Examples of pathologies associated with protein maturationdefect are cystic fibrosis (class 2 mutations), Wilson's disease,progressive familial intrahepatic cholestasis, nephrogenic diabetesinsipidus due to vasopressin receptor mutations.

As defined herein, a “pathology associated with protein trafficking” isa disease in which a protein, due to mutations affecting the proteinitself or other factors, remains trapped in an intermediate cellularcompartment (e.g. the endoplasmic reticulum) and therefore does notreach its final destination (e.g. plasma membrane). Mistrafficking maybe the consequence of misfolding that leads to detection by the qualitycontrol systems resulting in early degradation by the proteasome.Mistrafficking may be also due to defective interaction with ancillaryproteins required for coordinated trafficking. Examples of pathologiesassociated with protein maturation defect are cystic fibrosis (class 2mutations), Wilson's disease, progressive familial intrahepaticcholestasis, nephrogenic diabetes insipidus due to vasopressin receptormutations.

Preferred pathologies that may be treated with the compounds of thepresent invention are summarised in the following table:

Defect Pathology Comment Pathology associated with a defect in an ABC(ATP-binding cassette) transporter I. Genetic and non genetic diseasesassociated with altered CFTR activity in the lungs and/or other organsCFTR Cystic fibrosis mutations CFTR Congenital Bilateral More than halfof all men with CBAVD mutations Absence of Vas have mutations in theCFTR gene. Mutations Deferens (CBAVD) in this gene also cause cysticfibrosis. When CBAVD occurs with CFTR mutations, it is considered a formof atypical cystic fibrosis. CFTR obstructive Obstructive azoospermia(OA) results from mutations azoospermia mechanical blockage, which canoccur anywhere along the reproductive tract, including the vas deferens,epididymis, and ejaculatory. Link to CFTR mutations CFTR disseminatedObstructive multifactorial disorder belonging Mutations, bronchiectasisto the category of cystic fibrosis polymorphisms, monosymptomaticdiseases (or CFTR- dysfunction opathies) Association of bronchiectasiswith cystic fibrosis gene mutations and polymorphisms. The cysticfibrosis gene is also associated with bronchiectasis due to rheumatoidarthritis and allergic bronchopulmonary aspergillosis; see Semin RespirCrit Care Med. 2003 April; 24(2): 179-84. CFTR asthma See Can Respir J.2012 January-February; 19(1): 44-45. Mutations CFTR allergic pulmonaryIncreased risk in CF patients. mutations aspergillosis CFTR acute,chronic and/or Subjects with non-functional CFTR protein mutationsrecurrent and/or show clinical features of cystic fibrosis. Thoseautoimmune with less severe mutations in the CFTR gene pancreatitis riskdeveloping pancreatitis, which is estimated to be 40 to 80 times that inthe general population. Heterozygotes for CFTR mutations are generallyhealthy but still have a 3 to 4-fold risk over the general populationfor pancreatitis; see World J Gastroenterol. 2014 Dec. 7; 20(45): 16891-16901. chronic sinusitis Cystic fibrosis related, see Am J RhinolAllergy. 2013 September-October; 27(5): 387-395. smoking-related lungBeneficial effect due to thinning of mucus not pathology directly linkedto CFTR mutations. Correctors/potentiators may have beneficial effect indiseases characterized by mucus stasis, like smoke related lung diseaseand COPD CFTR Sjogren's syndrome Disorders with decreased function ofsalivary, expression lacrimal glands, and the exocrine pancreas; related(not CFTR expression found to be altered and necessarily with Transgeneexpression as well as Treatment mutation) with VX770 and, in particular,C18 restored salivation, rescued CFTR expression and localization, andnearly eliminated the inflammation and tissue damage; seeGastroenterology. 2017 October; 153(4): 1148- 1159. doi:10.1053/j.gastro.2017.06.011. Epub 2017 Jun. 19. CFTR-related sclerosingcholangitis Abnormalities in CFTR function/CFTR- disorder mediated iontransport dysfunction CFTR related panbronchiolites CFTR-relatedneonatal disorder hypertripsinemia Pulmonary Emphysema, as a consequenceof chronic emphysema obstructive lung disease, could benefit fromstabilization and enhanced function of CFTR protein II. Genetic diseasesin which a defective ABC transporter is involved ABCadrenoleukodystrophy transporter defect ABC Stargardt diseasetransporter defect ABC senile macular transporter degeneration defectABC Tangier disease transporter defect ABC progressive familialtransporter intrahepatic defect cholestasis ABC Dubin-Johnsontransporter syndrome defect ABC elastic transporter pseudoxanthomadefect ABC persistent transporter hyperinsulinemic defect hypoglycaemiaof infancy due to focal adenomatous hyperplasia III. Genetic diseasescaused by folding, degradation, and/or maturation defects leading toinstability of a mutant protein Limb-Girdle Application of smallmolecules developed to muscular dystrophy rescue F508del-CFTRtrafficking- CFTR (LGMD) correctors- improved the maturation of severalα-sarcoglycan mutants that were consequently rescued at the plasmamembrane. Remarkably, in myotubes from a patient with LGMD2D, treatmentwith CFTR correctors induced the proper re-localization of the wholesarcoglycan complex; see Carotti et al., Human Molecular Genetics,Volume 27, Issue 6, 15 Mar. 2018, Pages 969-984. Autosomal dominant LGMDis known as LGMD1 and there are currently recognized eight subtypes(LGMD1A-1H). Autosomal recessive LGMD is known as LGMD2 and has 17subtypes (LGMDA-Q). Additional terminology has been used in the past todescribe forms of muscular dystrophy that are now classified under LGMD.These terms are no longer widely used and include scapulohumeral (Erb)muscular dystrophy, pelvifemoral (Leyden-Mobius) muscular dystrophy, andsevere childhood autosomal recessive muscular dystrophy (SCARMD)muscular dystrophy See Carotti M, et al. Hum Mol Genet. 2018, of thecinguli 27, 969-984 nephrogenic diabetes See Sampson H M, et al.Orphanet J Rare Dis. insipidus 2013, 8, 11- cited at page 4 LQTS2 SeeSampson H M, et al. Orphanet J Rare Dis. 2013, 8, 11- cited at page 4congenital See Sampson H M, et al. Orphanet J Rare Dis. hyperinsulinism2013, 8, 11- cited at page 4 retinitis pigmentosa and “cone-rod” retinaldystrophy

Although many eukaryotic ABC-transporters use the energy derived fromATP hydrolysis to carry out an active transport of substances, otherswork differently. In the CFTR protein and in the sulfonylurea receptor(SUR), the ATP hydrolysis is associated with the regulation of theopening and closure of the same channel-protein (CFTR) or K⁺ channels(SUR).

Human ABC-transporters are involved in several diseases resulting frompolymorphisms in the ABC genes, and rarely due to the complete loss offunction of the individual ABC proteins. Of particular relevance arediseases due to ER-associated degradation (ERAD) of mutant ABC proteins.Misfolding and premature degradation caused by missense mutations hasbeen reported to be a significant cause of membrane proteindeficiencies. Disease causing mutations in several human ABC proteins,including among others ABCA1 (Tangier disease), ABCB4 (progressivefamilial intrahepatic cholestasis type 3), ABCB11 (progressive familialintrahepatic cholestasis type 2), ABCC2 (Dubin-Johnson syndrome), ABCC7(cystic fibrosis), ABCC8 (hyperinsulinemic hypoglycemia of infancy) andABCG2 (gout), have been linked to aberrant folding, retrotranslocationof proteins into the cytoplasm and subsequent proteasomal degradation(Rudashevskaya E L, et al. Drug Discov Today Technol 2014, 12, e87-e94).

Further ABC-related diseases include adrenoleukodystrophy, Stargardt'sdisease, immune deficiencies, elastic Pseudoxanthoma, persistenthyperinsulinemic hypoglycaemia of childhood. The human family ABCB(MDR/TAP) is responsible for multiresistance (MDR) against a variety ofstructurally unrelated drugs. Glycoprotein P ABCB1 or MDR1 is alsoinvolved in other biological processes, for which lipid transport is themain function. It mediates the secretion of aldosterone steroids fromthe adrenal glands and its inhibition has blocked the migration ofdendritic immune cells, probably related to the transport outwardly ofthe lipidic platelet activating factor (PAF).

The compounds of the present invention can also increase the activity ofmutated forms of CFTR gene, such as S549N, G542X, G551D, R117H, N1303K,W1282X, R553X, I507del, R1162X, G85E, D1152H, R560T, R347P, A455E,R334W, Q493X, E56K, P67L, R74W, D110E, D110H, R117C, G178R, E193K,L206W, R347H, R352Q, A455E, S549R, G551S, D579G, S945L, S997F, F1052V,K1060T, R1070, F1074L, G1244E, S1251N, S 1255P, D1270N, G1349D.

In a preferred embodiment, the compounds of the invention are intendedfor use in the treatment of patients carrying CFTR gene mutations of oneor more classes, e.g. class I, class II, class III, class IV, class V,or class VI mutations. The subjects can carry mutations in ahomozygosity (e.g. F508del/F508del), or compounded heterozygositycondition (e.g. F508del/G542X or F508del/N1303K). In fact, the chemicalcompounds of the present invention, although they are provided with amechanism of action which is typical for the correctors, can operate ondifferent mutation classes, since they are able to increase theproduction of mature CFTR protein. Preferably, in the specific case ofclass I mutations (e.g. G542X, or W1282X), the ability of combinationwith agents promoting the “read through” of the premature stop mutationis referred to.

In one embodiment, the compounds defined above are part of combinationsdesigned specifically for recovering the function of a mutated protein.

In a preferred embodiment, the compounds of the present inventionproduce a synergistic effect on the recovery of F508del-CFTR if combinedwith class 1 correctors, such as VX-809(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid), according to the terminology created by Okiyoneda et al.(Okiyoneda T, et al. Nat Chem Biol 2013, 9, 444-454). This synergisticaction is also expected for combinations including other correctors,e.g. but not limited to VX-661(1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide),VX-445, VX-659, VX-983, VX-152, VX-440 (Olacaftor,N-(benzenesulfonyl)-6-[3-fluoro-5-(2-methylpropoxy)phenyl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide)developed by Vertex Pharmaceuticals; ABBV-2737, GLPG2222 (Wang X, et al.J Med Chem. 2018, 61, 1436-1449), GLPG2851, GLPG2665, GLPG2737, GLPG3221developed by Galapagos/AbbVie; PTI-801 developed by ProteostasisTherapeutics; FDL169 developed by Flatley Discovery Lab;bisaminomethylthiazole known as corr-4a (Pedemonte N, et al. J ClinInvest. 2005, 115, 2564-2571); W1282Xcorr-B09 and W1282Xcorr-A23 (Haggieet al., J Biol Chem 2017, 292, 771-785).

In particular, a synergistic effect is expected for combinations whichinclude one of the active compounds described herein and one of thefollowing correctors: VX-661 (tezacaftor), VX-809 or GLPG-2222(Galapagos/AbbVie).

Positive effects are also expected from combinations comprisingpotentiators and/or amplifiers (Giuliano K A et al., SLAS Discov 2018,23, 111-121; Molinski S V, et al. EMBO Mol Med. 2017, 9, 1224-1243). Thepotentiators increase the probability of opening the CFTR channelscarried in the plasma membrane by the effect of the correctors. Theamplifiers instead increase the synthesis of the CFTR protein,regardless of the type of mutation, and therefore provide more“substrate” for the corrector activity (Giuliano K A et al., SLAS Discov2018, 23, 111-121).

Potentiators of interest for the present invention include, e.g., VX-770(Ivacaftor), VX-561 (deuterated form of VX-770), GLPG1837 (Van der PlasS E, et al. J Med Chem. 2018, 61, 1425-1435), GLPG 2545, GLPG 3067,genistein, phenylglycine (PG-01), PTI-808 (Proteostasis Therapeutics).Other potentiators, belonging to the families of 1,4-dihydropyridines,tetrahydrobenzothiophenes, benzofurans, anthraquinones, sulphonamidesand phenylglycines, have been previously identified by academiclaboratories by screening chemical “libraries” (Yang H, et al. J BiolChem 2003, 278, 35079-35085; Pedemonte N, et al. Mol Pharmacol 2005, 67,1797-1807; Pedemonte N, et al. Mol Pharmacol 2005, 68, 1736-1746).

Amplifiers of interest for the present invention include, e.g., PTI-428,(Proteostasis Therapeutics).

The combination of compounds of the invention and drugs that increasethe read-through of the premature stop codons, such as Ataluren (PTC124)(3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid) is also ofinterest for the present invention.

Correctors, potentiators, amplifiers of interest for the presentinvention are known in the art and, in particular, described in WO2017173274 (which is herein incorporated by reference). Compounds of thepresent invention may also be combined to inhibitors of HDAC which haveshown significant benefit in correcting protein misfolding diseases thatoccur in response to both familial and somatic mutation (see as areference Angles, F., Hutt, D. M., & Balch, W. E. (2019). HDACInhibitors Rescue Multiple Disease-Causing CFTR Variants. HumanMolecular Genetics. doi:10.1093/hmg/ddz02). HDAC inhibitors belinostat(PXD-101), panobinostat (LBH-589) and romidepsin (FK-228) have shownefficacy in improving the stability, trafficking and function of CFTRvariants alone or in combination with the CFTR corrector, VX-809. Inparticular, HDAC inhibitors can correct the trafficking defectassociated with Class II (ER export defective) and III/IV(gating/channel function defective) CFTR variants and restore cellsurface chloride channel activity in primary bronchial epithelial (hBE)cells homozygous for F508del.

Further, relevant for the present invention is the combination ofcompounds of the invention and gene therapy for replacing the mutatedgene with a functioning gene (classical gene therapy), or repairing themutated gene through, e.g., “gene editing” protocols.

The compounds described herein can also be combined with drugs that acton targets other than CFTR, but equally relevant for the multi-organpathology features of cystic fibrosis, especially for respiratorymanifestations. Among these drugs we can include:

i) antibiotics and anti-infectives such as penicillins (amoxicillin,clavulanic acid, cloxacillin, dicloxacillin, ticarcillin),cephalosporins (cephalexin, cefdinir, cefprozil, cefaclor, cefuroxime),sulfamethoxazole, trimethoprim, erythromycin, sulfisoxazole,azithromycin), tetracycline (tetracycline, doxycycline, minocycline, andtigecycline); vancomycin; imipenem, meropenem; colistimethate;aminoglycosides (tobramycin, amikacin, gentamicin); quinolones(ciprofloxacin, levofloxacin), aztreonam, linezolid upon oral,inhalation, intravenous, intramuscular administration;ii) anti-inflammatories: corticosteroids (inhaled or orally; e.g.budesonide, Clenil) and non-steroidal drugs (ibuprofen);iii) mucolytics: dornase alfa (Pulmozyme), N-acetylcysteine (Fluimucil),saline hypertonic, mannitol (Bronchitol);iv) bronchodilators: salbutamol, albuterol, levalbuterol.

An “active metabolite” is a modified form of a drug occurring when adrug is metabolized by the body into a form which continues to produceeffects in the body.

As used herein, the term “deuterated derivative” refers to an identicalchemical structure, in which one or more hydrogen atoms are replaced bya deuterium atom.

As used herein, the term “modulator” refers to a compound that increasesthe activity of a biological molecule, such as a protein, preferably amutated protein. For example, a protein modulator is a compound thatincreases the activity of that protein. The increase in activityresulting from a modulator includes but is not limited to compounds thatcorrect, enhance, stabilize and/or amplify the protein.

As used herein, the term “corrector” refers to an agent that promotesthe processing and trafficking of a biological molecule, such as aprotein, preferably a mutated protein, to increase the amount of suchbiological molecule on the surface of the cell. Preferably, thecompounds of the invention as defined above act as correctors, inparticular of the CFTR mutated protein.

As used herein, the term “potentiator” refers to an agent that increasesthe activity of a channel-protein, preferably in its mutated form,located on the surface of the cell, preferably resulting in an increasein ion transport.

In the present invention, the term “potentiator” also refers to an agentthat increases the probability of opening the channels of a biologicalmolecule, such as a protein, preferably a mutated protein. For mutationswhich cause a defect in protein maturation (e.g. F508del), the action ofpotentiators is preferably favoured by the correctors' effect.

As used herein, the term “active pharmaceutical ingredient” (“API”)refers to a biologically active compound.

In the present invention, the term “amplifier” refers to an agent thatincreases the synthesis of a biological molecule, preferably a protein,preferably a mutated protein, preferably regardless of the type ofmutation, thus providing more “substrate” for the activity of correctorsand potentiators.

The term “aryl” includes carbocyclic or heterocyclic hydrocarbonscontaining one to two rings, either fused or bound by a single bond, inwhich at least at least one of the rings is aromatic. Preferably, eachheterocyclic aromatic hydrocarbon, also referred to as heteroaryl group,comprises a 5- or 6-membered ring containing 1-3 heteroatoms selectedfrom N, O or S.

Examples of aryl groups according to the invention are, e.g., phenyl,biphenyl α- or β-naphthyl, dihydronaphthyl, thienyl, benzothienyl,furyl, benzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, tiazolyl,isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidyl,pyridazinil, indolyl, isoindolyl, purinyl, quinolyl, isoquinolyl,dihydroquinolyl, quinoxalinil, benzodioxolyl, indanil, indenyl,triazolyl, and the like. Preferably, aryl is phenyl.

As used herein, the term “heterocyclic” (also known as“heterocycloalkyl”) refers to a ring, preferably having 5 or 6 members,containing one or more heteroatoms from N, O, S. In particular, it ismeant a saturated or partially unsaturated 3- to 7-membered carbocyclicring, where one or more carbon atoms are replaced by heteroatoms, suchas nitrogen, oxygen and sulphur. Examples not limited to theheterocyclic groups are, e.g., piran, pyrrolidine, pyrroline,imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline,thiazolidine, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine,piperazine, morpholine, and the like.

The term “cycloalkyl”, unless otherwise specified, means a monocyclicring comprising 5 to 8 carbon atoms, which may contain one or moredouble bonds even if it does not have a completely conjugated 7 Lsystem. Examples of cycloalkyl groups, without limitation, arecyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene.

The term “linear or branched C1-C6 alkyl”, thus including C1-C4 alkyls,is understood to mean any group such as, e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tertbutyl, secbutyl, n-pentyl, n-hexyl,and the like. Preferably, alkyl is methyl.

The term “linear or branched C2-C6 alkenyl” is understood to mean anygroup such as, e.g., vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl, and the like.

The term “linear or branched C2-C6 alkynyl” is understood to mean anygroup such as, e.g., ethinyl, 2-propinyl, 4-pentinyl, and the like.

Preferably, arylalkyl is benzyl. Preferably, arylsulfonyl isphenylsulfonyl. Preferred examples of carboxylic ester include: COOEt,COOMe, COOiPr, COOtBu.

Preferred halogens include bromine, chlorine and iodine. Morepreferably, halogen is bromine.

The salts of the compounds of the present invention are also includedwithin the scope of the invention. Due to their potential use inmedicine, the salts of the compounds of formula (I) are preferablypharmaceutically acceptable. Pharmaceutically acceptable salts comprisethe conventional non-toxic salts obtained by saltification of a compoundof formula (I) with inorganic acids (e.g. hydrochloric, hydrobromic,sulfuric or phosphoric acid), or with organic acids (e.g. acetic,propionic, succinic acid, benzoic, sulfanylic, 2-acetoxy-benzoic,cinnamic, mandelic, salicylic, glycolic, lactic, oxalic, malic, maleic,malonic, fumaric, tartaric, citric, p-toluene sulphonic,methanesulphonic, ethanesulphonic, or naphthalensulphonic). For a reviewon suitable pharmaceutical salts, see: Berge S. M. et al., J. Pharm.Sci. 1977, 66, 1-19; Gould P. L. Int. J. Pharm 1986, 33, 201-217 andBighley et al. Encyclopedia of Pharmaceutical Technology, Marcel DekkerInc, New York 1996, Volume 13, page 453-497. Other pharmaceuticallyacceptable salts include pharmaceutically acceptable alkali or alkalineearth metal salts such as sodium, potassium, calcium or magnesium salts;in particular pharmaceutically acceptable salts of one or morecarboxylic acid groups which may be present in the compound of formula(I). Other salts, which are not pharmaceutically acceptable, e.g. thetrifluoroacetate salt, may be useful in the preparation of compounds ofthe present invention and these form a further aspect of the invention.The invention comprises in its scope all the possible stoichiometric andnon-stoichiometric forms of the salts of the compounds of formula (I).

Furthermore, the compounds of formula (I) can exist in unsolvated formsas well as in solvated form with pharmaceutically acceptable solventssuch as water, EtOH and the like. Some compounds of formula (I) mayexist in stereoisomeric forms (e.g., they may contain one or moreasymmetric carbon atoms). The individual stereoisomers (enantiomers anddiastereoisomers) and mixtures thereof are included in the scope of thepresent invention. The present invention also covers the individualisomers of the compounds represented by the formula (I) as mixtures withisomers in which one or more chiral centres are inverted. Racemicmixtures can be separated to give their individual enantiomer usingpreparative HPLC using a column with chiral stationary phase or resolvedto produce individual enantiomers using methods known to those skilledin the art. Furthermore, chiral intermediates can be resolved and usedto prepare single enantiomers.

Similarly, it is understood that the compounds of formula (I) can existin tautomeric forms different from those shown in the formula and theseare included in the scope of the present invention.

The invention also includes all suitable isotopic variations of acompound of the invention.

An isotopic variation of a compound of the invention is defined as thatin which at least one atom is replaced by an atom having the same atomicnumber but an atomic mass different from the atomic mass which isusually found in nature. Examples of isotopes that can be incorporatedinto the compounds of the invention include isotopes such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl respectively. Someisotopic variations of the invention, e.g., those in which a radioactiveisotope such as ³I or ¹⁴C is incorporated, are useful in tissue deliverystudies of the drug and/or substrate. Furthermore, replacement withisotopes such as deuterium ²H, can provide certain therapeuticadvantages resulting from greater metabolic stability. The isotopicvariations of the compounds of the invention can generally be preparedby conventional procedures as well as with the illustrative methods orwith the preparations described in the examples below by using suitableisotopic variations of the suitable reagents.

It will be appreciated by those skilled in the art that certainprotected derivatives of the compounds of the invention, which can bemade prior to a final deprotection step, cannot possess pharmacologicalactivity as such, but can, in certain cases, be administered orally orparenterally and then metabolized in the body to form compounds definedin the first aspect that are pharmacologically active. These derivativescan therefore be described as “prodrugs”. All protected derivatives,prodrugs, solvates, clathrates, pharmaceutically acceptable salts ofcompounds defined in the first aspect are included in the scope of theinvention. Examples of prodrugs suitable for the compounds of thepresent invention are described in Drug of Today, Volume 19, Number 9,1983, pp. 499-538 and in Topics in Chemistry, Chapter 31, pp. 306-316and in “Design of Prodrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1(the disclosure of which the document is incorporated therein byreference). It will be further appreciated by those skilled in the artthat certain moieties, known to those skilled in the art as“pro-moieties”, are described by H. Bundgaard, in “Design of Prodrugs”(the disclosure of which the document is incorporated therein byreference) can be positioned on appropriate functionalities when thesefeatures are present within the compound defined in the first aspect.

The pharmaceutical compositions of the present invention can be selectedbased on the treatment requirements. These compositions are prepared byadmixing and are suitably adapted for oral or parenteral administration,and as such they can be administered in the form of tablets, capsules,oral preparations, powders, granules, pills, injectable or infusibleliquid solutions, suspensions, suppositories, preparation forinhalation.

In particular, a pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable salt, solvate, clathrate,prodrug, tautomer, stereoisomer, deuterated derivative, activemetabolite thereof can be administered in a variety of ways, includingparenteral, oral, pulmonary, ophthalmic, nasal, rectal, vaginal,auditory, topical, buccal, transdermal, intravenous, intramuscular,subcutaneous, intradermal, intraocular, intracerebral, intralymphatic,intraarticular, intrathecal and intraperitoneal routes. Thepharmaceutical compositions of the present invention are particularlysuitable for pulmonary, intranasal and/or ocular administration.

In addition to the common meaning attributed to the routes describedherein for administration to any part, tissue or organ whose primaryfunction is the gas exchange with the external environment, for thepurposes of the present invention, “pulmonary” also includes a tissue ora cavity which it is contingent on the respiratory tract, particularlybreasts, even more particularly paranasal sinuses. For pulmonaryadministration, an aerosol formulation comprising the compound of theinvention, a manual pump spray, a nebulizer or a pressurized doseinhaler (meter-dose inhaler) as well as dry powder formulations areprovided by way of non-limiting example. Suitable formulations of thistype may also include other agents, such as antistatic agents, to keepthe described compounds in the form of effective aerosols.

A drug delivery device for dispensing and delivering an aerosol cancomprise an aerosol container with a dosage valve containing apharmaceutical aerosol formulation as described and a housing for anactuator adapted to contain the container and allow the delivery anddelivery of the drug. The container in said device can have a head spacethat represents more than about 15% of the total volume of thecontainer. Often, the compound intended for pulmonary administration isdissolved, suspended or emulsified in a mixture of solvent, surfactantand propellant. The mixture can be kept under pressure in a sealedcontainer with a metering valve.

Tablets and capsules for oral administration are generally presented inunit dosage form and contain conventional excipients such as binders,fillers (including cellulose, mannitol, lactose), diluents, tabletagents, lubricants (including magnesium stearate), detergents,disintegrants (e.g. polyvinylpyrrolidone and starch derivatives such assodium starch glycolate), dyes, flavourings and wetting agents (e.g.sodium lauryl sulphate).

The oral solid compositions can be prepared by conventional mixing,filling or pelleting methods. The mixing operation can be repeated todistribute the active ingredient in all the compositions containinglarge quantities of fillers. These operations are conventional.

Oral liquid preparations may be in the form of, e.g., aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product to be reconstituted with water or with asuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, e.g. sorbitol, syrup,methylcellulose, gelatine, hydroxyethyl cellulose,carboxymethylcellulose, aluminium stearate gel or hydrogenated ediblefats; emulsifying agents, e.g. lecithin, sorbitan monooleate, or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters such as glycerine esters,propylene glycol, or ethyl alcohol; preservatives, such as methyl orpropyl p-hydroxybenzoate or sorbic acid, and if desired, conventionalflavouring or colouring agents. Oral formulations also includeconventional slow release formulations such as coated gastro-resistanttablets or granules.

The pharmaceutical preparation for administration via inhalation can beprovided by an insufflator or a pressure nebulizer.

For parenteral administration the fluid unit dosage can be prepared,comprising the compound and a sterile vehicle. The compound can besuspended or dissolved, depending on the vehicle and concentration.Parenteral solutions are normally prepared by dissolving the compound ina vehicle, sterilization by filtration of the latter, filling ofsuitable bottles and sealing. Advantageously, adjuvants such as localanaesthetics, preservatives and buffering agents can be dissolved in thevehicle. To increase stability, the composition can be frozen afterfilling the vials and removing the water under vacuum. The parenteralsuspensions are prepared in substantially the same way, except that thecompound may be suspended in the vehicle instead of being dissolved andsterilized by exposure to ethylene oxide prior to suspension in thesterile vehicle. Conveniently, a surfactant or a wetting agent may beincluded in the composition to promote uniform distribution of thecompound of the invention.

For oral or sublingual administration, the compositions can be tablets,pastilles, or gels.

The compounds can be pharmaceutically formulated as suppositories orretention enemas, e.g. suppositories containing conventional bases suchas cocoa butter, polyethylene glycol, or other glycerides, for rectaladministration.

Another route of administration of the compounds of the presentinvention relates to topical treatment. Topical formulations maycontain, e.g., ointments, creams, lotions, gels, solutions, pastesand/or may contain liposomes, micelles and/or microspheres. Examples ofointments comprise oily ointments such as vegetable oils, animal fats,semisolid hydrocarbons, emulsifiable ointments such as hydroxystearinsulphate, anhydrous lanolin, hydrophilic petrolatum, cetyl alcohol,glycerol monostearate, stearic acid, water-soluble ointments containingpolyethylene glycols of various molecular weight. The creams, as knownto the experts in the formulation, are viscous liquids or semisolidemulsions, and contain an oily phase, an emulsifier and an aqueousphase. The oily phase generally contains petrolatum and an alcohol suchas cetyl or stearic alcohol. The formulations suitable for topicalocular administration also include eye drops, in which the activeingredient is dissolved or suspended in a suitable vehicle, inparticular in an aqueous solvent for the active ingredient.

A further way of administering the compounds of the invention concernstransdermal delivery. Typical transdermal formulations compriseconventional aqueous and non-aqueous vectors, such as creams, oils,lotions or pastes or they can be in the form of medicated membranes orplasters.

In order to increase bioavailability, the compounds can be formulatedpharmaceutically in liposomes or in nanoparticles. Acceptable liposomescan be neutral, negatively or positively charged, the charge being afunction of the charge of the liposome components and of the pH of theliposomal solution. Liposomes can normally be prepared using a mixtureof phospholipids and cholesterol. Suitable phospholipids includephosphatidylcholine, phosphatidylethanolamine, phosphatidic acid,phosphotidylglycerol, phosphatidylinositol. Polyethylene glycol can beadded to improve the blood circulation time of liposomes.

Acceptable nanoparticles include albumin nanoparticles and goldnanoparticles.

A reference for the formulations is the book by Remington (Remington“The Science and Practice of Pharmacy”, Lippincott Williams & Wilkins,2000).

The compounds of the present invention can be used for use in thetreatment and/or prevention of the above-mentioned pathologies as a soletherapy or in combination with further therapeutic agents. Thecombination can be administered as a separate (simultaneous, sequential)composition of the individual components of the treatment or as a singledosage form containing both agents. When the compounds of the presentinvention are in combination with other active principles, the activeingredients can be formulated separately in preparations for a singleingredient of one of the forms described above, and then given ascombined preparations, which are administered simultaneously or severaltimes, or can be formulated together in a two or more ingredientpreparation.

The compounds of general formula (I) can be administered to a patient ata total daily dose of, e.g., from 0.001 to 1000 mg/kg of body weight perday. The compositions of the dosage units can contain quantities ofsub-multiples thereof to compensate for the daily dose. The compound canalso be administered weekly or any other day. Determining the optimaldosages for a particular patient is well known to those skilled in theart. As is common practice, compositions are normally accompanied byinstructions for use written or printed in the treatment in question.

The present invention will be described by non-limiting examples, withreference to the following figures:

FIG. 1. Evaluation of the corrective efficacy of a compound of theinvention, PP007. The plot shows an example of an experiment where theactivity of F508del-CFTR was evaluated in CFBE41o− cells with the HS-YFPfluorescent probe. Activity is reported as “quenching rate” (QR) ofcellular fluorescence following the addition of iodide in theextracellular saline solution. The extent of the iodide flow, whichoccurs through the CFTR protein, reflects the efficacy of the correctivetreatment. The figure also shows the two parameters (QR_(TOT) andQR_(VX)) used to calculate the “additivity index” (AI) reported in thevarious tables to describe the compounds' efficacy. The cells weretreated for 24 h with PP007 at the indicated concentrations, with andwithout VX-809 (1 μM). As control, cells were treated for 24 h withvehicle alone (dimethylsufoxide, DMSO) at the same concentration (0.1%)used to add test compounds.

FIG. 2. Comparison of analogues of the compound PP007. The correctiveactivity was evaluated in CFBE41o− cells as described in FIG. 1. Thecells were treated for 24 hours with the compounds indicated at twoconcentrations (1 and 10 μM) in the presence and absence of thecorrector VX-809 (1 μM). As control, cells were treated for 24 h withvehicle alone (dimethylsufoxide, DMSO) at the same concentration (0.1%)used to add test compounds.

FIG. 3. PP008 corrective activity on primary epithelial cells. (A) Therepresentative plots and (B) the bar chart show the results obtained bytreating bronchial epithelial cells from a patient homozygous for themutation F508del with PP008 (10 μM) in the presence and absence ofVX-809 (1 μM). As control, cells were treated for 24 h with vehiclealone (dimethylsufoxide, DMSO) at the same concentration (0.1%) used toadd test compounds. The activity of F508del-CFTR, represented by theresponse to the specific inhibitor inh-172, is significantly increasedby treatment with PP008, especially in combination with VX-809. *,p<0.05; ***, p<0.001. As shown at the bottom of the plot in panel A,treatment with PP008 does not modify the calcium-dependent chloridesecretion, activated and inhibited with UTP and inh-A01, respectively.(C) Results obtained on nasal epithelial cells of a homozygous F508delpatient. *, p<0.05; ***, p<0.001.

FIG. 4. Evaluation of trimethylangelicin (TMA) corrective activity. Theassay (HS-YFP) was performed on CFBE41o− cells treated with TMA andPP008 (with and without VX-809 1 μM) at the indicated concentrations. Ascontrol, cells were treated for 24 h with vehicle alone(dimethylsufoxide, DMSO) at the same concentration (0.1%) used to addtest compounds.

FIG. 5. Analysis of F508del-CFTR maturation by immunoblot (IB). Theimage shows a representative experiment where electrophoretic mobilityof F508del-CFTR was determined in lysates of CFBE41o− cells treated for24 hr with vehicle (DMSO), VX-809 (1 μM) alone, or VX-809 (1 μM)combined with PP008, PP028 or PP034 (10 μM). The protein migrates asband B (150 kDa, core-glycosylated immature form) or band C (170 kDa,fully-glycosylated mature form). Detection of beta-actin from the samesamples is also shown. Treatment of cells with PP008, PP028, or PP034markedly enhances the abundance of the mature form of the protein withrespect to VX-809 alone.

FIG. 6. Analysis of F508del-CFTR localization by immunofluorescence.CFBE41o− cells were treated for 24 hr vehicle (DMSO, control), withVX-809 (1 μM), or with VX-809 (1 μM) plus PP028 (10 μM). Cells were thenfixed and stained with an antibody against CFTR. Arrows show regionswhere CFTR signal appears at the cell periphery in agreement with plasmamembrane localization.

FIG. 7. Effect of a compound of the invention on the G542X prematurestop codon mutation. The scatter dot plot shows data obtained with theHS-YFP assay in null CFBE41o− cells (cells with negligible expression ofF508del-CFTR). Cells were cotransfected with HS-YFP and one of thefollowing plasmids: empty (mock), G542X-CFTR, wild type CFTR. Whereindicated, cells expressing G542X-CFTR were also treated with DMSO(control), G418 0.5 mg/ml alone, or G418 in combination with VX-809 (1μM), with PP028 (10 μM), or with VX-809 plus PP028 (1 and 10 μM,respectively). Each dot reports the activity from a separate experiment.Mean and SD are also reported for each group of data. ***, p<0.001 vs.untreated cells. #, p<0.05 vs. G418 alone. ###, p<0.001 vs. G418 alone.

DETAILED DESCRIPTION OF THE INVENTION Chemical Synthesis General

According to a further aspect of the invention there is provided aprocess for the preparation of compounds of formula (I). The followingschemes are examples of synthetic schemes that may be used to synthesisethe compounds of the invention. In the following schemes reactive groupscan be protected with protecting groups and deprotected according towell established techniques. In the following schemes substituents areas defined herein above for formula (I), unless otherwise indicated. Itwill be understood by those skilled in the art that certain compounds ofthe invention can be converted into other compounds of the inventionaccording to standard chemical methods.

A synthetic route optimized for the synthesis of the compounds of theinvention containing the pyrrole core and the corresponding ketoneprecursors is described in general schemes 1 and 2 below. Ketones offormula 6 and 7, which can be functionalised at the α-carbonyl position,are ideal precursors for the synthesis of the compounds of theinvention. In particular the 1,4,5,6-tetrahydro-7H-indolones (6a n=1)and 4,5,6,7-tetrahydrocyclohepta[b]pyrrol-8 (1H)-ones (6b n=2) can beobtained according to synthetic pathways previously reported by theinventors, via multistep sequences that involve the anellation of thecarbocyclic portion of substituted pyrroles of formula 3 (Spanò V, etal. Eur J Med Chem 2017, 128, 300-318; Spanò V, et al. Eur J Med Chem2016, 123, 447-461; P. Barraja, et al. Bioorg Med Chem 2010, 18,4830-4843). In particular, the compounds of formula 4, 5 and 6 and somecompounds of formula 7-12 can be prepared according to methodspreviously reported by the authors.

By means of a selective acylation with AlCl₃ and succinic or glutaricanhydride derivatives 4a (n=2) (90-100%) and 4b (n=3) (80-95%) areobtained. The reduction of the carbonyl to methylene according to theClemmensen method or with triethylsilane in trifluoroacetic acid allowsthe isolation of pyrrole of formula 5a (n=3) (70-75%) and 5b (n=4)(75-94%). The closure of the hexa- or hepta-cyclic ring on the freeposition 5 of the pyrrole, with trifluoroacetic anhydride leads to thecompounds 6a,b with excellent yields (85-90%) (Scheme 1).

The alkyl- or aralkyl-substituted derivatives 7a,b, can be prepared byalkylation reactions starting from the corresponding NH-type derivatives6a,b, carried out in solvents such as anhydrous THF or DMF and alkyl- orarylalkyl-halides as electrophiles.

Compounds of formula 7a with R¹=COOEt and 7b with R¹=COOEt can besubjected to hydrolysis in basic media in ethanol generating thecarboxyacid derivatives 7c (R¹=COOH) which can be converted intoisopropyl esters 7d (e.g. R¹=COOiPr) in isopropanol,4-dimethylaminopyridine (DMAP) andN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC).Alternatively compounds 7c (R¹=COOH) can be transformed into thecorresponding carboxyamide derivatives 7e (R¹=CONHR^(a)) by activationof the carboxyacid functionality withN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) andsubsequent reaction with the proper amine in the presence ofN,N-diisopropylethylamine (DIPEA) and 1-hydroxybenzotriazole (HOBt).Compounds of formula 7a (R¹=ester such as COOEt) can also be subjectedto chlorination or iodination using N-chlorosuccinimide (NCS) orN-iodosuccinimide (NIS).

Scheme 2 refers to the synthesis of pyrrolo[3,2-h]quinolin-2-ones (n=1),pyrrolo[3,2-h]quinolinones 13 and 14 and cyclohepta[b]pyrrol-8 (1H)-one(n=2) as reported in Tables 1, la and 2. Functionalization in α-carbonylposition of compounds of formula 7 can be obtained by directintroduction of the enaminic group using acetal amides such asdimethylformamide dimethylacetale (DMFDMA) ort-butoxy-bis(dimethylamino)methane (TBDMAM) with conventionalreflux-heating in solvents such as toluene or DMF (Method A) or with theaid of microwave irradiation (Method B) (Power 50 W; Time 20-40 min; 100psi; Temperature 120° C.) in dimethyl formamide (DMF) to give thecorresponding enamino ketones 8. Prolonging heating time (24 h) indimethyl formamide dimethylacetale (DMFDMA) (Method C), in the case of4-methylbenzyl ketones (compound 7 with R=4-MeBn) and 2-methylbenzyl(compound 7 with R=2-MeBn), leads to transesterification of the2-ethoxycarbonyl function to 2-methoxycarbonyl.Carboxymethyl-substituted enaminone derivatives 8 (R¹=COOMe) thusobtained, can then be subjected to the same cyclization conditionsdescribed below allowing to obtain the corresponding tricyclic compoundsof formula 9^((#)) (Scheme 2).

Intermediates 8 reacted with cyanomethylene compounds selected as 1,3dinucleophiles, in particular benzene sulfonyl acetonitriles, cyclizeafter prolonged reflux to give tricyclic derivatives of formula 9, seeTable 1 and 2. The subsequent methylation of the annular amidic functionleads to the N-methyl (10) and O-methyl substituted derivatives (11)formed in the same reaction mixture, indicating the existence of thetautomeric equilibrium between the ketonic and enolic form in thereaction solvent. The introduction of halogen atoms (e.g. R2=Br, I) atposition R² can be obtained by reaction with Br₂, in anhydrousdichloromethane (DCM) or I₂ in anhydrous N,N-dimethylformamide in thepresence of potassium hydroxide. In the latter case instead of the iododerivative 12^(({circumflex over ( )})), the oxidation compound of thetricyclic scaffold was isolated from the reaction mixture afterchromatographic purification 13 (PP058, Table 1a), which wassubsequently subjected to bromination to give the derivative 14 (PP057,Table 1a).

Compounds 9^((#)) and 12^(({circumflex over ( )})) where R¹ is an estercan be converted into the corresponding carboxyacid derivatives(R¹=COOH) by basic hydrolysis and then transformed into thecorresponding carboxyamide derivatives (R¹=CONHR^(a)) by activation ofthe carboxyacid functionality withN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) andsubsequent reaction with ammonium carbonate or the proper amine in thepresence of N,N-diisopropylethylamine (DIPEA) and 1-hydroxybenzotriazole(HOBt).

An exemplary set of derivatives synthesised according to Schemes 1-2 isshown in Tables 1-2 below, along with their additivity index (AI %),which was measured as described in the Materials and Methods section.Table 1 refers to compounds of formula 9-12 in which n=1, while Table 2refers to compounds of formula 9-12 in which n=2. The compound PP058 andits brominated analogue PP057, reported as compounds of formula 13 and14 in Scheme 2, are reported in Table 1a.

TABLE 1 Pyrrolo[3,2-h]quinolinones AI^(a) AI^(a) CPD R R¹ R² R³ (%) CPDR R¹ R² R³ (%) PP007(#) 4-MeBn COOEt — SO2Ph 169 PP076({circumflex over( )}) 4-MeBn COOEt Cl SO2Ph 244 PP008({circumflex over ( )}) 4-MeBnCOOEt Br SO2Ph 207 PP077({circumflex over ( )}) 4-MeBn COOEt I SO2Ph 202PP010(#) Me COOEt — SO2Ph 95 PP078(#) 4-MeBn COOH H SO2Ph 37 PP011(#) BnCOOEt — SO2Ph 150 PP079({circumflex over ( )}) 4-MeBn COOH Br SO2Ph 38PP015({circumflex over ( )}) 2-MeBn COOEt H SO2Ph 124 PP080(#) 4-MeBnCONH2 H SO2Ph 2 PP016({circumflex over ( )}) 3-MeBn COOEt H SO2Ph 42PP081({circumflex over ( )}) 3-MeBn COOH Br SO2Ph 20 PP017({circumflexover ( )}) 4-ClBn COOEt H SO2Ph 203 PP082({circumflex over ( )}) 3-MeBnCONH2 Br SO2Ph 31 PP019({circumflex over ( )}) 4-MeBn COOMe H SO2Ph 29PP083(#) 3-MeBn CONHiPr H SO2Ph 53 PP020({circumflex over ( )}) 2-MeBnCOOMe H SO2Ph 33 PP084(#) 3-MeBn CONHcyclopropyl H SO2Ph 10PP021({circumflex over ( )}) 2,4-diMeBn COOEt H SO2Ph 40PP086({circumflex over ( )}) 4-MeBn CONHiPr Br SO2Ph 116PP022({circumflex over ( )}) 4-MeBn COOi-Pr H SO2Ph 279PP089({circumflex over ( )}) 4-MeBn CONH2 Br SO2Ph 11 PP023({circumflexover ( )}) 4-MeBn COOEt H SO2Ph-4-Me 89 PP090(#) 3-MeBn COOH H SO2Ph 36PP024({circumflex over ( )}) 4-MeBn COOEt H SO2Me 11 PP091({circumflexover ( )}) 3-MeBn CONHiPr Br SO2Ph 208 PP025({circumflex over ( )})3,4-diMeBn COOEt H SO2Ph 178 PP092({circumflex over ( )}) 3-MeBnCONHcyclopropyl Br SO2Ph 52 PP027({circumflex over ( )}) 2-MeBn COOEt BrSO2Ph 185 PP093(#) 3-MeBn CONH2 H SO2Ph 25 PP028({circumflex over ( )})3-MeBn COOEt Br SO2Ph 278 PP094(#) 3,4-Me2Bn COOH H SO2Ph 47PP029({circumflex over ( )}) 4-ClBn COOEt Br SO2Ph 46 PP095({circumflexover ( )}) 3,4-Me2Bn COOH Br SO2Ph 11 PP030({circumflex over ( )})4-MeBn COOEt Br 4-ClSO2Ph 96 PP096(#) 4-BrBn CONHiPr H SO2Ph 3PP031({circumflex over ( )}) 4-MeBn COOMe Br SO2Ph 39 PP097({circumflexover ( )}) 4-BrBn CONHiPr Br SO2Ph 99 PP032({circumflex over ( )})2-MeBn COOMe Br SO2Ph 133 PP098(#) 4-BrBn CONHcyclopropyl H SO2Ph 4PP033({circumflex over ( )}) 2,4-diMeBn COOEt Br SO2Ph 114PP099({circumflex over ( )}) 4-BrBn CONHcyclopropyl Br SO2Ph 82PP034({circumflex over ( )}) 4-MeBn COOi-Pr Br SO2Ph 261PP100({circumflex over ( )}) 3-MeBn CONHSO2Ph Br SO2Ph 47PP035({circumflex over ( )}) 4-MeBn COOEt Br SO2Ph-4-Me 56PP101({circumflex over ( )}) 3-MeBn CONHt-But Br SO2Ph 249PP036({circumflex over ( )}) 4-MeBn COOEt Br SO2Me 23 PP102({circumflexover ( )}) 3-MeBn CONHt-Butisoxzole Br SO2Ph 103 PP037({circumflex over( )}) 3,4-diMeBn COOEt Br SO2Ph 335 PP103(#) 3-MeBn COOiPr H SO2Ph 284PP060(#) 4-BrBn COOEt H SO2Ph 148 PP104({circumflex over ( )}) 3-MeBnCOOiPr Br SO2Ph 374 PP062(#) 4-IBn COOEt H SO2Ph 95 PP105(#)cyclopropyl- COOiPr H SO2Ph 174 methyl PP063({circumflex over ( )})4-IBn COOEt Br SO2Ph 146 PP106({circumflex over ( )}) cyclopropyl-COOiPr Br SO2Ph 277 methyl PP064(#) cyclopropylmethyl COOEt H SO2Ph 235PP107(#) 4-FBn COOiPr H SO2Ph 335 PP065({circumflex over ( )})cyclopropylmethyl COOEt Br SO2Ph 284 PP108({circumflex over ( )}) 4-FBnCOOiPr Br SO2Ph 257 PP066(#) 6-methylpyridin- COOEt H SO₂Ph 62PP067({circumflex over ( )}) 6-methylpyridin- COOEt Br SO₂Ph 81(3-yl)methyl (3-yl)methyl PP068(#) 2,4,6-(Me)3Bn COOEt H SO₂Ph 116PP069({circumflex over ( )}) 2,4,6-(Me)3Bn COOEt Br SO₂Ph 175 PP070(#)4-CF₃Bn COOEt H SO₂Ph 101 PP071({circumflex over ( )}) 4-CF₃Bn COOEt BrSO₂Ph 35 PP072(#) 4-FBn COOEt H SO₂Ph 420 PP073({circumflex over ( )})4-FBn COOEt Br SO₂Ph 442 PP075({circumflex over ( )}) CH₂CH₂CH₂—N(Me)₂COOEt Br SO₂Ph 34 (#)Compounds of formula 9 in Scheme 2; (§) Compoundsof formula 10 in Scheme 2; (*) Compounds of formula 11 in Scheme 2;({circumflex over ( )})Compounds of formula 12 in Scheme 2 ^(a)Activityof compounds (at 10 μM) was expressed as additivity index (AI %) whichis calculated as (QR_(TOT) − QR_(VX))/QR_(VX) where QR_(TOT) is thequenching rate (HS-YFP assay) in the presence of test compound plusVX-809 and QR_(VX) is the quenching rate with VX-809 alone.

TABLE 1a Pyrrolo[3,2-h]quinolinones corresponding to compounds offormula 13 and 14 in Scheme 2 CPD R R¹ R² R³ AI^(a) 13 (PP057) 4-MeBnCOOEt H SO₂Ph 272% 14 (PP058) 4-MeBn COOEt Br SO₂Ph 177% ^(a)Activity ofcompounds (at 10 μM) was expressed as additivity index (AI %) which iscalculated as (QR_(TOT) − QR_(VX))/QR_(VX) where QR_(TOT) is thequenching rate (HS-YFP assay) in the presence of test compound plusVX-809 and QR_(VX) is the quenching rate with VX-809 alone.

TABLE 2 Pyrrolo[3′,2′:6,7]cyclohepta[1,2-6]pyridin-9(1H)-ones CPD R R¹R² R³ AI^(a) PP048(#) 4-MeBn COOEt — SO₂Ph 22% PP056({circumflex over( )}) 4-MeBn COOEt Br SO₂Ph 60% (#)Compounds of formula 9 in Scheme 2;({circumflex over ( )})Compounds of formula 12 in Scheme 2 ^(a)Activityof compounds (at 10 μM) was expressed as additivity index (AI %) whichis calculated as (QR_(TOT) − QR_(VX))/QR_(VX) where QR_(TOT) is thequenching rate (HS-YFP assay) in the presence of test compound plusVX-809 and QR_(VX) is the quenching rate with VX-809 alone.

A detailed description of the synthesis of exemplary compounds producedaccording to Schemes 1 and 2 is provided hereinbelow.

General Procedure for the Synthesis of 1,4,5,6-tetrahydro-7H-indolones(7a n=1) e 4,5,6,7-tetrahydrocyclohepta[b]pyrrole-8 (1H)-ones (7b n=2)1-Substituted

To a solution of the suitable ketones 6a,b (15 mmol) in anhydrous THF orDMF (20 mL), NaH (0.64 g, 16 mmol) was added at 0° C. and the reactionmixture was stirred at room temperature for 1 h. Then the suitable alkylor aralkyl halide was added at (16 mmol). The reaction mixture wasstirred at room temperature or heated at reflux up to completeness(TLC). Then the reaction mixture was poured onto crushed ice and theprecipitate was filtered off and dried, in absence the solution wasextracted with DCM (3×30 mL). The organic layer was dried over Na₂SO₄and the solvent was removed under reduced pressure. The crude productwas purified by chromatography (DCM) giving the desired ketones.

Ethyl1-(2-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with2-methylbenzyl chloride in DMF after 24 h at room temperature: lightbrown solid; yield: 80%; m.p.: 123-124° C.; IR: 1709 (CO), 1653 (CO)cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.31 (3H, t, J=7.1 Hz, CH₃), 2.00-2.13 (2H,m, CH₂), 2.27 (3H, s, CH₃), 2.52 (2H, t, J=6.0 Hz, CH₂), 2.75 (2H, t,J=6.0 Hz, CH₂), 4.27 (2H, q, J=7.1 Hz, CH₂), 6.07 (2H, s, CH₂), 6.78(1H, s, H-3), 6.97-7.08 (4H, m, H-3′, H-4′, H-5′ and H-6′); ¹³C nmr(CDCl₃) (ppm): 14.3 (q), 21.1 (q), 23.7 (t), 24.6 (t), 40.2 (t), 49.1(t), 60.7 (t), 115.1 (d), 126.7 (2×d), 128.0 (s), 129.0 (2×d), 130.2(s), 135.6 (s), 135.9 (s), 136.5 (s), 161.0 (s), 190.5 (s). Anal calcdfor C₁₉H₂₁NO₃: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.41; H, 6.65; N,4.43.

Ethyl1-(3-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with3-methylbenzyl chloride in DMF after 24 h at room temperature: colorlessoil; yield: 65%; IR: 1711 (CO), 1656 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm):1.30 (3H, t, J=7.1 Hz, CH₃), 2.01-2.14 (2H, m, CH₂), 2.28 (3H, s, CH₃),2.53 (2H, t, J=6.0 Hz, CH₂), 2.76 (2H, t, J=6.0 Hz, CH₂), 4.26 (2H, q,J=7.1 Hz, CH₂), 6.08 (2H, s, CH₂), 6.80-7.16 (4H, m, H-3, H-2′, H-4′,H-5′ and H-6′); ¹³C nmr (CDCl₃) (ppm): 14.2 (q), 21.5 (q), 23.7 (t),24.6 (t), 40.2 (t), 49.3 (t), 60.7 (t), 115.1 (d), 123.5 (d), 127.3 (d),127.7 (d), 128.1 (s), 128.2 (d), 130.3 (s), 135.6 (s), 137.8 (s), 138.8(s), 160.9 (s), 190.5 (s). Anal calcd for C₁₉H₂₁NO₃: C, 73.29; H, 6.80;N, 4.50. Found: C, 73.14; H, 6.53; N, 4.69.

Ethyl1-(4-chlorobenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carbossilato.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with4-chlorobenzyl chloride in DMF after 3 h at room temperature: whitesolid; yield: 70%; m.p.: 91-92° C.; IR: 1710 (CO), 1653 (CO) cm⁻¹; ¹Hnmr (CDCl₃) (ppm): 1.31 (3H, t, J=7.1 Hz, CH₃), 2.02-2.14 (2H, m, CH₂),2.53 (2H, t, J=6.0 Hz, CH₂), 2.76 (2H, t, J=6.0 Hz, CH₂), 4.27 (2H, q,J=7.1 Hz, CH₂), 6.06 (2H, s, CH₂), 6.81 (1H, s, H-3), 7.04 (2H, d, J=8.5Hz, H-2′ and H-6′), 7.22 (2H, d, J=8.5 Hz, H-3′ and H-4′); ¹³C nmr(CDCl₃) (ppm): 14.2 (q), 23.6 (t), 24.5 (t), 40.1 (t), 48.8 (t), 60.8(t), 115.3 (d), 127.9 (s), 128.2 (2×d), 128.5 (2×d), 130.1 (s), 132.7(s), 135.8 (s), 137.3 (s), 160.9 (s), 190.6 (s). Anal calcd forC₁₈H₁₈ClNO₃: C, 65.16; H, 5.47; N, 4.22. Found: C, 65.01; H, 5.69; N,4.09.

Ethyl1-(2,4-dimethylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with2,4-dimethylbenzyl chloride in DMF after 24 h at room temperature: whitesolid; yield: 65%; m.p.: 102-103° C.; IR: 1712 (CO), 1653 (CO) cm⁻¹; ¹Hnmr (DMSO-d₆) (ppm): 1.18 (3H, t, J=7.1 Hz, CH₃), 1.93-2.05 (2H, m,CH₂), 2.19 (3H, s, CH₃), 2.29 (3H, s, CH₃), 2.44 (2H, t, J=5.6 Hz, CH₂),2.76 (2H, t, J=5.6 Hz, CH₂), 4.15 (2H, q, J=7.1 Hz, CH₂), 5.88-5.92 (3H,m, CH₂ and Ar), 6.79 (1H, d, J=7.9 Hz, Ar), 6.88 (1H, s, Ar), 6.98 (1H,s, Ar); ¹³C nmr (DMSO-d₆) (ppm): 13.9 (q), 18.5 (q), 20.4 (q), 22.9 (t),24.1 (t), 39.5 (t), 47.0 (t), 60.4 (t), 114.9 (d), 123.0 (d), 126.5 (d),127.4 (s), 129.9 (s), 130.3 (d), 133.7 (s), 134.4 (s), 135.1 (s), 135.3(s), 160.0 (s), 189.9 (s). Anal calcd for C₂₀H₂₃NO₃: C, 73.82; H, 7.12;N, 4.30. Found: C, 73.99; H, 7.01; N, 4.44.

Ethyl1-(3,4-dimethylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with3,4-dimethylbenzyl chloride in DMF after 24 h at room temperature: lightyellow oil; yield: 60%; IR: 1710 (CO), 1654 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.23 (3H, t, J=6.0 Hz, CH₃), 1.92-2.04 (2H, m, CH₂), 2.13 (6H, s,2×CH₃), 2.47 (2H, t, J=6.0 Hz, CH₂), 2.73 (2H, t, J=6.0 Hz, CH₂), 4.21(2H, q, J=6.0 Hz, CH₂), 5.93 (2H, s, CH₂), 6.60 (1H, d, J=8.0 Hz, Ar),6.79-6.82 (2H, m, Ar), 6.99 (1H, d, J=8.0 Hz, Ar); ¹³C nmr (DMSO-d₆)(ppm): 14.0 (q), 18.9 (q), 19.5 (q), 22.9 (t), 24.1 (t), 39.6 (t), 48.3(t), 60.5 (t), 115.0 (d), 123.3 (d), 127.1 (s), 127.3 (d), 129.4 (d),129.7 (s), 134.6 (s), 135.3 (s), 135.9 (s), 136.1 (s), 160.2 (s), 190.0(s). Anal calcd for C₂₀H₂₃NO₃: C, 73.82; H, 7.12; N, 4.30. Found: C,73.75; H, 6.95; N, 4.59.

Ethyl1-[(4-methylphenyl)methyl]-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole-2-carboxylate.This compound was obtained by reaction of ethyl8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole-2-carboxylate 6b(R¹=COOEt) with 4-methylbenzyl chloride in DMF after 24 h at roomtemperature: white solid; yield 67%; m.p.: 72-73° C.; IR: 1715 (CO),1649 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.30 (3H, t, J=7.1 Hz, CH₃),1.77-1.84 (4H, m, 2×CH₂), 2.27 (3H, s, CH₃), 2.60-2.66 (2H, m, CH₂),2.77-2.83 (2H, m, CH₂), 4.25 (2H, q, J=7.1 Hz, CH₂), 6.07 (2H, s, CH₂),6.80 (1H, s, H-3), 6.88 (2H, d, J=8.0 Hz, H-3″ and H-5″), 7.04 (2H, d,J=8.0 Hz, H-2″ and H-6″); ¹³C nmr (CDCl₃) (ppm): 14.2 (q), 21.1 (q),21.3 (t), 24.8 (t), 25.8 (t), 42.0 (t), 48.8 (t), 60.6 (t), 117.7 (d),126.2 (2×d), 127.0 (s), 129.0 (2×d), 133.5 (s), 134.0 (s), 136.2 (s),136.3 (s), 160.8 (s), 194.6 (s). Anal calcd for C₂₀H₂₃NO₃: C, 73.82; H,7.12; N, 4.30. Found: C, 73.64; H, 7.38; N, 4.22.

Ethyl1-[(4-bromophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with4-bromobenzyl chloride in DMF after 24 h at room temperature: whitesolid; yield: 78%; m.p.: 75-76° C.; IR: 1715 (CO), 1658 (CO) cm⁻¹; ¹Hnmr (DMSO-d₆) (ppm): 1.21 (3H, t, J=7.1 Hz, CH₃), 1.90-2.05 (2H, m,CH₂), 2.47 (2H, t, J=5.8 Hz, CH₂), 2.73 (2H, t, J=5.8 Hz, CH₂), 4.20(2H, q, J=7.1 Hz, CH₂), 5.94 (2H, s, CH₂), 6.85 (1H, s, H-3), 6.91 (2H,d, J=8.3 Hz, H-2′ and H-6′), 7.47 (2H, d, J=8.3 Hz, H-3′ and H-5′); ¹³Cnmr (DMSO-d₆) (ppm): 14.0 (q), 22.8 (t), 24.1 (t), 39.5 (t), 48.3 (t),60.6 (t), 115.1 (d), 119.9 (s), 127.0 (s), 128.3 (2×d), 129.7 (s), 131.2(2×d), 135.5 (s), 138.2 (s), 161.1 (s), 190.1 (s). Anal calcd forC₁₈H₁₈BrNO₃: C, 57.46; H, 4.82; N, 3.72. Found: C, 57.33; H, 4.69; N,3.84.

Ethyl1-[(4-iodophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with4-iodobenzyl chloride in DMF after 24 h at room temperature: whitesolid; yield: 55%; m.p.: 95-96° C.; IR: 1709 (CO), 1658 (CO) cm⁻¹; ¹Hnmr (DMSO-d₆) (ppm): 1.22 (3H, t, J=7.1 Hz, CH₃), 1.92-2.09 (2H, m,CH₂), 2.47 (2H, t, J=5.5 Hz, CH₂), 2.73 (2H, t, J=5.5 Hz, CH₂), 4.20(2H, q, J=7.1 Hz, CH₂), 5.93 (2H, s, CH₂), 6.77 (2H, d, J=8.3 Hz, H-2′and H-6′), 6.85 (1H, s, H-3), 7.63 (2H, d, J=8.3 Hz, H-3′ and H-5′); ¹³Cnmr (DMSO-d₆) (ppm): 14.0 (q), 22.9 (t), 24.1 (t), 39.5 (t), 48.4 (t),60.6 (t), 92.7 (s), 115.1 (d), 127.0 (s), 128.4 (2×d), 129.7 (s), 135.5(s), 137.0 (2×d), 138.6 (s), 160.1 (s), 190.1 (s). Anal calcd forC₁₈H₁₈INO₃: C, 51.08; H, 4.29; N, 3.31. Found: C, 50.92; H, 4.11; N,3.47.

Ethyl1-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with(chloromethyl)cyclopropane in DMF after 5 h at room temperature: yellowoil; yield: 60%; IR: 1715 (CO), 1664 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):0.31-0.38 (4H, m, 2×CH₂), 1.14-1.32 (4H, m, CH₃ e CH), 1.91-2.03 (2H, m,CH₂), 2.48 (2H, t, J=6.1 Hz, CH₂), 2.70 (2H, t, J=6.1 Hz, CH₂), 4.26(2H, q, J=7.1 Hz, CH₂), 4.64 (2H, d, J=7.1 Hz, CH₂), 6.75 (1H, s, H-3);¹³C nmr (DMSO-d₆) (ppm): 3.0 (2×t), 12.8 (d), 14.0 (q), 22.9 (t), 24.1(t), 39.7 (t), 49.1 (t), 60.5 (t), 114.7 (d), 126.7 (s), 129.4 (s),135.2 (s), 160.5 (s), 190.0 (s). Anal calcd for C₁₅H₁₉NO₃: C, 68.94; H,7.33; N, 5.36. Found: C, 69.08; H, 7.21; N, 5.24.

Ethyl1-[(6-methylpyridin-3-yl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with5-(chloromethyl)-2-methylpyridine in DMF after 8 h at room temperature:light brown solid; yield: 65%; m.p.: 64-65° C.; IR: 1715 (CO), 1658 (CO)cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.23 (3H, t, J=7.1 Hz, CH₃), 1.94-2.06(2H, m, CH₂), 2.40-2.49 (5H, m, CH₃ and CH₂), 2.73 (2H, t, J=5.9 Hz,CH₂), 4.22 (2H, q, J=7.1 Hz, CH₂), 5.95 (2H, s, CH₂), 6.84 (1H, s, H-3),7.12-7.28 (2H, m, H-4′ and H-5′), 8.15 (1H, s, H-2′); ¹³C nmr (DMSO-d₆)(ppm): 14.0 (q), 22.8 (t), 23.6 (q), 24.0 (t), 39.5 (t), 46.4 (t), 60.6(t), 115.2 (d), 122.7 (d), 127.0 (s), 129.6 (s), 131.0 (s), 134.4 (d),135.6 (s), 147.1 (d), 156.5 (s), 160.2 (s), 190.2 (s). Anal calcd forC₁₈H₂₀N₂O₃: C, 69.21; H, 6.45; N, 8.97. Found: C, 69.14; H, 6.64; N,9.09.

Ethyl7-oxo-1-[(2,4,6-trimethylphenyl)methyl]-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with2,4,6-trimetthylbenzyl chloride in DMF after 24 h at room temperature:yellow oil; yield: 67%; IR: 1715 (CO), 1652 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.08 (3H, t, J=7.1 Hz, CH₃), 1.85-2.03 (8H, m, 2×CH₃ and CH₂),2.15 (3H, s, CH₃), 2.46 (2H, t, J=6.2 Hz, CH₂), 2.72 (2H, t, J=6.2 Hz,CH₂), 4.06 (2H, q, J=7.1 Hz, CH₂), 5.76 (1H, s, H-3), 5.94 (2H, s, CH₂),6.72 (2H, s, H-3′ and H-5′); ¹³C nmr (DMSO-d₆) (ppm): 13.8 (q), 19.1(2×q), 20.2 (q), 23.0 (t), 24.2 (t), 39.6 (t), 45.8 (t), 60.4 (t), 114.2(d), 128.8 (s), 129.3 (2×d), 130.4 (s), 131.4 (s), 135.0 (s), 135.2 (s),135.6 (2×s), 160.4 (s), 190.3 (s). Anal calcd for C₂₁H₂₅NO₃: C, 74.31;H, 7.42; N, 4.13. Found: C, 74.22; H, 7.61; N, 3.95.

Ethyl7-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with4-trifluoromethylbenzyl chloride in DMF after 24 h at room temperature:white solid; yield: 78%; m.p.: 56-57° C.; IR: 1709 (CO), 1652 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.20 (3H, t, J=7.1 Hz, CH₃), 1.97-2.08 (2H, m,CH₂), 2.44 (2H, t, J=5.5 Hz, CH₂), 2.75 (2H, t, J=5.5 Hz, CH₂), 4.19(2H, q, J=7.1 Hz, CH₂), 6.06 (2H, s, CH₂), 6.88 (1H, s, H-3), 7.14 (2H,d, J=8.1 Hz, H-2′ and H-6′), 7.65 (2H, d, J=8.1 Hz, H-3′ and H-5′); ¹³Cnmr (DMSO-d₆) (ppm): 13.9 (q), 22.8 (t), 24.0 (t), 39.4 (t), 48.7 (t),60.6 (t), 115.2 (d), 125.3 (2×d), 125.3 (s), 126.6 (2×d), 127.1 (s),127.7 (s), 129.7 (s), 135.6 (s), 145.5 (d, J_(C-F)=284.0 Hz), 161.2 (s),190.1 (s). Anal calcd for C₁₉H₁₈F₃NO₃: C, 62.46; H, 4.97; N, 3.83.Found: C, 62.60; H, 5.09; N, 3.77.

Ethyl1-[(4-fluorophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with4-fluorobenzyl chloride in DMF after 24 h at room temperature: whitesolid; yield: 62%; m.p.: 72-73° C.; IR: 1726 (CO), 1658 (CO) cm⁻¹; ¹Hnmr (DMSO-d₆) (ppm): 1.22 (3H, t, J=7.1 Hz, CH₃), 1.89-2.07 (2H, m,CH₂), 2.47 (2H, t, J=5.8 Hz, CH₂), 2.72 (2H, t, J=5.8 Hz, CH₂), 4.20(2H, q, J=7.1 Hz, CH₂), 5.96 (2H, s, CH₂), 6.83 (1H, s, H-3), 7.00-7.12(4H, m, H-2′, H-3′, H-5′ and H-6′); ¹³C nmr (DMSO-d₆) (ppm): 14.4 (q),23.3 (t), 24.5 (t), 40.0 (t), 48.5 (t), 61.0 (t), 115.4 (d), 115.6 (2×d,J_(C3′-F)=16.2 Hz), 127.5 (s), 128.7 (2×d, J_(C2′-F)=8.2 Hz), 130.1 (s),135.3 (s), 136.0 (s), 160.0 (s), 161.9 (d, J_(C4′-F)=191.5 Hz), 190.6(s). Anal calcd for C₁₈H₁₈FNO₃: C, 68.56; H, 5.75; N, 4.44. Found: C,68.69; H, 5.51; N, 4.31.

Ethyl1-[3-(dimethylamino)propyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 6a (R¹=COOEt) with4-fluorobenzyl chloride in DMF after 3-chloro-N,N-dimethylpropan-1-aminein DMF after 16 h at 60° C.: yellow oil; yield: 50%; IR: 1709 (CO), 1652(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.28 (3H, t, J=7.1 Hz, CH₃),1.76-1.80 (2H, m, CH₂), 1.90-2.02 (2H, m, CH₂), 2.10-2.30 (8H, m, 2×CH₃and CH₂), 2.46 (2H, t, J=6.0 Hz, CH₂), 2.68 (2H, t, J=6.0 Hz, CH₂), 4.26(2H, q, J=7.1 Hz, CH₂), 4.61-4.68 (2H, m, CH₂), 6.71 (1H, s, H-3); ¹³Cnmr (DMSO-d₆) (ppm): 14.1 (q), 22.9 (t), 24.1 (t), 29.0 (t), 39.5 (t),44.6 (t), 45.0 (2×q), 56.4 (t), 60.4 (t), 114.2 (d), 127.1 (s), 129.5(s), 134.9 (s), 160.2 (s), 189.7 (s). Anal calcd for C₁₆H₂₄N₂O₃: C,65.73; H, 8.27; N, 9.58. Found: C, 65.57; H, 8.16; N, 9.69.

General Procedure for the Synthesis of1-Substituted-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid 7c(R¹=COOH)

To a solution of ethyl1-substituted-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (6.4mmol) in ethanol (25 mL) an aqueous solution of KOH 50% (4.8 mL) wasadded and the reaction mixture was heated at reflux up to completeness(TLC). After cooling, the solvent was removed under reduced pressure Theresidue was added of water and the solution was acidified with HCl 6M.The solid formed was filtered off and dried.

1-(4-Methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid.This compound was obtained by reaction of ethyl1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 7a(R¹=COOEt) after 3 h: white solid; yield: 98%; m.p.: 191-192° C.; IR:3136 (OH), 1722 (CO), 1613 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.89-2.06(2H, m, CH₂), 2.23 (3H, s, CH₃), 2.45 (2H, t, J=6.0 Hz, CH₂), 2.72 (2H,t, J=6.0 Hz, CH₂), 5.98 (2H, s, CH₂), 6.78 (1H, s, H-3), 6.85 (2H, d,J=8.0 Hz, H-2′ and H-6′), 7.06 (1H, d, J=8.0 Hz, H-3′ and H-5′), 13.04(1H, s, OH); ¹³C nmr (DMSO-d₆) (ppm): 20.6 (q), 22.9 (t), 24.1 (t), 39.5(t), 48.1 (t), 114.9 (d), 126.1 (2×d), 128.1 (s), 128.8 (2×d), 129.4(s), 135.4 (s), 135.8 (s), 136.0 (s), 161.9 (s), 189.9 (s). Anal calcdfor C₁₇H₁₇NO₃: C, 72.07; H, 6.05; N, 4.94. Found: C, 72.19; H, 5.89; N,4.76.

1-[(3-Methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid. This compound was obtained by reaction of ethyl1-(3-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 7a(R¹=COOEt) after 2 h: white solid; yield: 99%; m.p: 154-155° C.; IR:3131 (OH), 1692 (CO), 1658 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.89-2.23(2H, m, CH₂), 2.45 (2H, t, J=6.0 Hz, CH₂), 2.73 (2H, t, J=6.0 Hz, CH₂),5.99 (2H, s, CH₂), 6.65-6.79 (3H, m, H-3 and Ar), 7.02-7.14 (2H, m, Ar),13.05 (1H, s, OH); ¹³C nmr (DMSO-d₆) (ppm): 21.4 (q), 22.9 (t), 24.2(t), 39.5 (t), 48.4 (t), 114.9 (d), 123.0 (d), 126.7 (d), 127.4 (d),128.1 (s), 128.2 (d), 129.5 (s), 135.3 (s), 137.3 (s), 139.0 (s), 161.9(s), 189.9 (s). Anal calcd for C₁₇H₁₇NO₃: C, 72.07; H, 6.05; N, 4.94.Found: C, 72.22; H, 6.16; N, 4.82.

1-[(4-Bromophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid. This compound was obtained by reaction of ethyl1-[(4-bromophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) after 1 h: white solid; yield: 99%; m.p.: 195-196° C.; IR:3131 (OH), 1723 (CO), 1614 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.91-2.06(2H, m, CH₂), 2.45 (2H, t, J=6.0 Hz, CH₂), 2.72 (2H, t, J=6.0 Hz, CH₂),5.96 (2H, s, CH₂), 6.80 (1H, s, H-3), 6.91 (2H, d, J=8.3 Hz, H-2′ andH-6′), 7.47 (2H, d, J=8.3 Hz, H-3′ and H-6′), 13.13 (1H, s, OH); ¹³C nmr(DMSO-d₆) (ppm): 22.9 (t), 24.1 (t), 39.5 (t), 48.1 (t), 115.0 (d),119.8 (s), 128.0 (s), 128.3 (2×d), 129.4 (s), 131.2 (2×d), 135.5 (s),138.4 (s), 161.8 (s), 189.9 (s). Anal calcd for C₁₆H₁₄BrNO₃: C, 55.19;H, 4.05; N, 4.02. Found: C, 55.33; H, 4.17; N, 3.90.

1-(Cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid. This compound was obtained by reaction of ethyl1-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) after 1 h: white solid; yield: 99%; m.p.: 173-174° C.; IR:3096 (OH), 1692 (CO), 1664 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 0.29-0.39(4H, m, 2×CH₂), 1.14-1.27 (1H, m, CH), 1.93-2.01 (2H, m, CH₂), 2.46 (2H,t, J=6.1 Hz, CH₂), 2.69 (2H, t, J=6.1 Hz, CH₂), 4.65 (2H, d, J=7.0 Hz,CH₂), 6.70 (1H, s, H-3), 13.01 (1H, s, OH); ¹³C nmr (DMSO-d₆) (ppm): 3.5(2×t), 13.4 (d), 23.4 (t), 24.6 (t), 40.2 (t), 49.4 (t), 115.1 (d),128.3 (s), 129.7 (s), 135.6 (s), 162.6 (s), 190.4 (s). Anal calcd forC₁₃H₁₅NO₃: C, 66.94; H, 6.48; N, 6.00. Found: C, 67.08; H, 6.60; N,5.88.

1-[(4-Fluorophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid. This compound was obtained by reaction of ethyl1-[(4-fluorophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) after 2 h: white solid; yield: 99%; m.p.: 205-206° C.; IR:3136 (OH), 1715 (CO), 1623 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.88-2.07(2H, m, CH₂), 2.46 (2H, t, J=5.6 Hz, CH₂), 2.72 (2H, t, J=5.6 Hz, CH₂),5.99 (2H, s, CH₂), 6.79 (1H, s, H-3), 7.01-7.12 (4H, m, H-2′, H-3′, H-5′and H-6′), 13.08 (1H, s, OH); ¹³C nmr (DMSO-d₆) (ppm): 23.4 (t), 24.6(t), 40.0 (t), 48.3 (t), 115.4 (d), 115.6 (2×d, J_(C3′-F)=12.7 Hz),128.5 (s), 128.7 (2×d, J_(C2′-F)=8.2 Hz), 129.9 (s), 135.6 (s), 136.0(s), 161.1 (d, J_(C4′-F)=179.0 Hz), 163.2 (s), 190.4 (s). Anal calcd forC₁₆H₁₄FNO₃: C, 66.89; H, 4.91; N, 4.88. Found: C, 67.01; H, 5.05; N,4.73.

Synthesis of propan-2-yl1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate

To a solution of1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid(0.71 mmol) in a mixture of 2-propanol (10 mL) and xylene (10 mL)concentrated H₂SO₄ (0.8 mL) was added and the reaction mixture washeated at reflux for 48 h. After cooling, the solvent was removed underreduced pressure. The crude product was purified by chromatography (DCM)to give the desired ketone. White solid; yield: 89%; m.p.: 79-80° C.;IR: 1708 (CO), 1654 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.18 (3H, s, CH₃),1.21 (3H, s, CH₃), 1.89-2.04 (2H, m, CH₂), 2.19 (3H, s, CH₃), 2.43 (2H,t, J=5.8 Hz, CH₂), 2.66 (2H, t, J=5.8 Hz, CH₂), 5.00-5.12 (1H, m, CH),5.98 (2H, s, CH₂), 6.69 (1H, s, H-3), 6.89-7.00 (4H, m, H-2′, H-3′, H-5′and H-6′); ¹³C nmr (CDCl₃) (ppm): 21.1 (q), 21.9 (q), 23.7 (t), 24.6(t), 40.2 (t), 49.1 (t), 68.3 (d), 115.0 (d), 126.7 (2×d), 128.5 (s),129.0 (2×d), 130.1 (s), 135.6 (s), 135.9 (s), 136.4 (s), 160.5 (s),190.5 (s). Anal calcd for C₂₀H₂₃NO₃: C, 73.82; H, 7.12; N, 4.30. Found:C, 73.99; H, 7.01; N, 4.55.

General Procedure for the Synthesis of propan-2-yl1-substituted-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 7d

To a solution of the suitable acid derivatives 7c (5.3 mmol) ini-propanol (50 mL), DMAP (2.72 g, 22.3 mmol) and EDC (1.5 g, 7.8 mmol)were added and the reaction mixture was stirred at room temperature for16 h. Then the solvent was removed under reduced pressure and water andcrushed ice were added. The aqueous solution was extracted with ethylacetate (3×50 mL). The organic layers were dried over Na₂SO₄ and thesolvent removed under reduced pressure. The crude product was purifiedby chromatography column (DCM).

Propan-2-yl1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid 7c (R¹=COOH): white solid; yield: 87%; m.p.: 81-82° C.; IR: 1715(CO), 1658 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.18 (6H, d, J=5.7 Hz,2×CH₃), 1.95-2.04 (2H, m, CH₂), 2.22 (3H, s, CH₃), 2.37-2.48 (2H, m,CH₂), 2.63-2.79 (2H, m, CH₂), 4.95-5.11 (1H, m, CH), 5.96 (2H, s, CH₂),6.64-7.20 (5H, m, H-3, H-2′, H-4′, H-5′ and H-6′); ¹³C nmr (DMSO-d₆)(ppm): 21.0 (q), 21.4 (2×q), 22.9 (t), 24.1 (t), 39.6 (t), 48.6 (t),68.0 (d), 115.0 (d), 122.9 (d), 126.6 (d), 127.4 (d), 127.6 (s), 128.2(d), 129.6 (s), 135.4 (s), 137.3 (s), 138.8 (s), 159.7 (s), 190.0 (s).Anal calcd for C₂₀H₂₃NO₃: C, 73.82; H, 7.12; N, 4.30. Found: C, 73.97;H, 7.01; N, 4.46.

Propan-2-yl1-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of1-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid 7c (R¹=COOH): colorless oil; yield: 56%; IR: 1709 (CO), 1652 (CO)cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 0.28-0.39 (4H, m, 2×CH₂), 1.14-1.29 (7H,m, 2×CH₃ and CH), 1.92-2.00 (2H, m, CH₂), 2.46 (2H, t, J=5.9 Hz, CH₂),2.69 (2H, t, J=5.9 Hz, CH₂), 4.63 (2H, d, J=7.1 Hz, CH₂), 5.04-5.13 (1H,m, CH), 6.71 (1H, s, H-3); ¹³C nmr (DMSO-d₆) (ppm): 3.4 (2×t), 13.3 (d),22.0 (2×q), 23.4 (t), 24.6 (t), 40.2 (t), 49.5 (t), 68.4 (d), 115.1 (d),127.7 (s), 129.8 (s), 135.6 (s), 160.5 (s), 190.4 (s). Anal calcd forC₁₆H₂₁NO₃: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.64; H, 7.51; N,4.93.

Propan-2-yl1-[(4-fluorophenyl)methy]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of1-[(4-fluorophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid 7c (R¹=COOH): white solid; yield: 84%; m.p.: 100-101° C.; IR: 1715(CO), 1658 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.21 (6H, d, J=6.1 Hz,2×CH₃), 1.91-2.04 (2H, m, CH₂), 2.47 (2H, t, J=5.6 Hz, CH₂), 2.71 (2H,t, J=5.6 Hz, CH₂), 4.90-5.17 (1H, m, CH), 5.97 (2H, s, CH₂), 6.81 (1H,s, H-3), 6.99-7.13 (4H, m, H-2′, H-3′, H-5′ and H-6′); ¹³C nmr (DMSO-d₆)(ppm): 21.9 (2×q), 23.4 (t), 24.6 (t), 40.0 (t), 48.5 (t), 68.6 (d),115.4 (d), 115.5 (2×d, J_(C3′-F)=16.3 Hz), 127.8 (s), 128.6 (2×d,J_(C2′-F)=8.1 Hz), 130.0 (s), 135.4 (s), 136.0 (s), 161.7 (d,J_(C4′-F)=225.2 Hz), 190.5 (s). Anal calcd for C₁₉H₂₀FNO₃: C, 69.29; H,6.12; N, 4.25. Found: C, 69.38; H, 6.01; N, 4.17.

General Procedure for the Synthesis of1-Substituted-7-oxo-N-Substituted-4,5,6,7-tetrahydro-1H-indole-2-carboxamide7e

To a suspension of the suitable acid derivatives 7c (1.9 mmol) inanhydrous DMF (6 mL) N,N-diisopropylethylamine (1.9 mL, 10.9 mmol),1-hydroxybenzotriazole hydrate (0.41 g, 3.0 mmol), and EDC (0.53 g, 2.8mmol) were added. The reaction mixture was stirred at room temperaturefor 10 min. Then the proper amine (7.6 mmol) was added in one portion,and the resulting suspension was stirred at room temperature up tocompleteness (TLC). Then the reaction mixture was poured onto crushedice and the solid formed was filtered off, dried and used in the nextstep without further purification.

1-[(3-Methylphenyl)methyl]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction of1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid 7c (R¹=COOH) with isopropyl amine after 1 h: white solid; yield:55%; m.p.: 181-182° C.; IR: 3291 (NH), 1653 (CO), 1632 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.08 (6H, d, J=6.2 Hz, 2×CH₃), 1.90-2.03 (2H, m, CH₂),2.22 (3H, s, CH₃), 2.42 (2H, t, J=6.0 Hz, CH₂), 2.70 (2H, t, J=6.0 Hz,CH₂), 3.90-4.08 (1H, m, CH), 5.95 (2H, s, CH₂), 6.59 (1H, s, H-3),6.77-7.16 (4H, m, H-2′, H-4′, H-5′ and H-6′), 8.24 (1H, d, J=7.2 Hz,NH); ¹³C nmr (DMSO-d₆) (ppm): 21.0 (q), 22.1 (2×q), 23.1 (t), 24.3 (t),39.4 (t), 40.5 (d), 47.8 (t), 110.4 (d), 123.8 (d), 127.3 (d), 127.4(d), 127.5 (s), 128.1 (d), 132.6 (s), 135.6 (s), 137.2 (s), 139.2 (s),160.2 (s), 189.2 (s). Anal calcd for C₂₀H₂₄N₂O₂: C, 74.04; H, 7.46; N,8.64. Found: C, 74.18; H, 7.37; N, 8.55.

N-cyclopropyl-1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction of1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid 7c (R¹=COOH) with cyclopropylamine after 2 h: white solid; yield:50%; m.p.: 184-185° C.; IR: 3385 (NH), 1652 (CO), 1635 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 0.41-0.73 (4H, m, 2×CH₂), 1.93-2.05 (2H, m, CH₂), 2.23(3H, s, CH₃), 2.42 (2H, t, J=6.0 Hz, CH₂), 2.67-2.81 (3H, m, CH₂ andCH), 5.96 (2H, s, CH₂), 6.60 (1H, s, H-3), 6.74 (2H, t, J=7.5 Hz, Ar),6.85 (1H, s, H-2′), 6.98-7.17 (2H, m, Ar), 8.45 (1H, d, J=3.8 Hz, NH);¹³C nmr (DMSO-d₆) (ppm): 5.7 (2×t), 21.1 (q), 22.6 (d), 23.1 (t), 24.3(t), 39.4 (t), 47.9 (t), 110.6 (d), 123.5 (d), 127.1 (d), 127.4 (d),127.8 (s), 128.1 (d), 132.0 (s), 135.5 (s), 137.2 (s), 139.2 (s), 162.1(s), 189.2 (s). Anal calcd for C₂₀H₂₂N₂O₂: C, 74.51; H, 6.88; N, 8.69.Found: C, 74.67; H, 6.97; N, 8.54.

1-[(4-Methylphenyl)methyl]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction of1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid7c (R¹=COOH) with isopropylamine after 2 h: white solid; yield: 50%;m.p.: 183-184° C.; IR: 3245 (NH), 1671 (CO), 1645 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.09 (6H, d, J=6.6 Hz, 2×CH₃), 1.89-2.03 (2H, m, CH₂),2.22 (3H, s, CH₃), 2.42 (2H, t, J=5.8 Hz, CH₂), 2.69 (2H, t, J=5.8 Hz,CH₂), 3.91-4.08 (1H, m, CH), 5.94 (2H, s, CH₂), 6.61 (1H, s, H-3), 6.92(2H, d, J=7.9 Hz, H-3′ and H-5′), 7.04 (2H, d, J=7.9 Hz, H-2′ and H-6′),8.27 (1H, d, J=7.9 Hz, NH); ¹³C nmr (DMSO-d₆) (ppm): 20.6 (q), 22.1(2×q), 23.1 (t), 24.3 (t), 39.4 (t), 40.5 (d), 47.6 (t), 110.5 (d),126.7 (2×d), 127.5 (s), 128.7 (2×d), 132.5 (s), 135.6 (s), 135.9 (s),136.3 (s), 160.1 (s), 189.1 (s). Anal calcd for C₂₀H₂₄N₂O₂: C, 74.04; H,7.46; N, 8.64. Found: C, 73.92; H, 7.31; N, 8.79.

N-cyclopropyl-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction of1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid7c (R¹=COOH) with cycloproprylamine after 1 h: white solid; yield: 51%;m.p.: 186-187° C.; IR: 3268 (NH), 1669 (CO), 1641 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 0.49-0.53 (2H, m, CH₂), 0.62-0.71 (2H, m, CH₂),1.93-1.98 (2H, m, CH₂), 2.23 (3H, s, CH₃), 2.42 (2H, t, J=5.8 Hz, CH₂),2.66-2.80 (3H, m, CH₂ and CH), 5.95 (2H, s, CH₂), 6.60 (1H, s, H-3),6.91 (2H, d, J=7.9 Hz, H-3′ and H-5′), 7.05 (2H, d, J=7.9 Hz, H-2′ andH-6′), 8.44 (1H, d, J=3.9 Hz, NH); ¹³C nmr (DMSO-d₆) (ppm): 5.7 (2×t),20.6 (q), 22.6 (d), 23.6 (t), 24.3 (t), 39.4 (t), 47.7 (t), 110.7 (d),126.6 (2×d), 127.8 (s), 128.7 (2×d), 131.9 (s), 135.5 (s), 135.9 (s),136.3 (s), 162.1 (s), 189.2 (s). Anal calcd for C₂₀H₂₂N₂O₂: C, 74.51; H,6.88; N, 8.69. Found: C, 74.77; H, 6.79; N, 8.54

1-[(4-Bromophenyl)methyl]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction of1-[(4-bromophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid 7c (R¹=COOH) with isopropylamine after 1 h: white solid; yield:77%; m.p.: 170-171° C.; IR: 3291 (NH), 1652 (CO), 1636 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.08 (6H, d, J=6.5 Hz, 2×CH₃), 1.91-2.03 (2H, m, CH₂),2.42 (2H, t, J=5.5 Hz, CH₂), 2.70 (2H, t, J=5.5 Hz, CH₂), 3.90-4.03 (1H,m, CH), 5.93 (2H, s, CH₂), 6.67 (1H, s, H-3), 6.97 (2H, d, J=8.3 Hz,H-2′ and H-6′), 7.46 (2H, d, J=8.3 Hz, H-3′ and H-5′), 8.26 (1H, d,J=7.6 Hz, NH); ¹³C nmr (DMSO-d₆) (ppm): 22.1 (2×q), 23.1 (t), 24.3 (t),39.3 (t), 40.6 (d), 47.7 (t), 110.6 (d), 119.9 (s), 127.6 (s), 128.8(2×d), 131.0 (2×d), 132.2 (s), 135.7 (s), 138.7 (s), 159.9 (s), 189.2(s). Anal calcd for C₁₉H₂₁BrN₂O₂: C, 58.62; H, 5.44; N, 7.20. Found: C,58.55; H, 5.31; N, 7.33.

1-[(4-Bromophenyl)methyl]-N-cyclopropyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction of1-[(4-bromophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylicacid 7c (R¹=COOH) with cyclopropylamine after 1 h: white solid; yield:77%; m.p.: 178-179° C.; IR: 3296 (NH), 1669 (CO), 1629 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 0.46-0.70 (4H, m, 2×CH₂), 1.12-1.23 (1H, m, CH),1.91-2.00 (2H, m, CH₂), 2.42 (2H, t, J=6.3 Hz, CH₂), 2.66 (2H, t, J=6.3Hz, CH₂), 5.94 (2H, s, CH₂), 6.68 (1H, s, H-3), 6.95 (2H, d, J=8.3 Hz,H-2′ and H-6′), 7.46 (2H, d, J=8.3 Hz, H-3′ and H-5′), 8.49 (1H, d,J=4.0 Hz, NH); ¹³C nmr (DMSO-d₆) (ppm): 5.7 (2×t), 22.6 (d), 23.0 (t),24.2 (t), 39.3 (t), 47.7 (t), 110.8 (d), 119.8 (s), 127.8 (s), 128.7(2×d), 131.1 (2×d), 131.6 (s), 135.7 (s), 138.7 (s), 161.9 (s), 189.3(s). Anal calcd for C₁₉H₁₉BrN₂O₂: C, 58.93; H, 4.95; N, 7.23. Found: C,59.02; H, 5.06; N, 7.11.

General Procedure for the Synthesis of ethyl3-Substituted-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7f

To a solution1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (4.5mmol) in acetic acid (12 mL) NCS or NIS (4.5 mmol) was added and thereaction mixture was stirred at room temperature or at 60° C. up tocompleteness (TLC). Then the reaction mixture was poured onto crushedice and the aqueous solution was extracted with ethyl acetate (3×50 mL).The organic layers were dried over Na₂SO₄ and the solvent removed underreduced pressure. The crude product was purified by chromatographycolumn (Petroleum ether/AcOEt 95:5).

Ethyl3-chloro-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 7a(R¹=COOEt) with N-chlorosuccinimide after 5 h at 60° C.: white solid;yield: 50%; m.p.: 54-55° C.; IR: 1709 (CO), 1669 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.21 (3H, t, J=7.1 Hz, CH₃), 1.95-2.07 (2H, m, CH₂),2.23 (3H, s, CH₃), 2.52 (2H, t, J=5.9 Hz, CH₂), 2.67 (2H, t, J=5.9 Hz,CH₂), 4.24 (2H, q, J=7.1 Hz, CH₂), 5.93 (2H, s, CH₂), 6.84 (2H, d, J=8.0Hz, H-3′ and H-5′), 7.08 (2H, d, J=8.0 Hz, H-2′ and H-6′); ¹³C nmr(DMSO-d₆) (ppm): 13.8 (q), 20.6 (q), 20.9 (t), 23.1 (t), 39.4 (t), 48.9(t), 61.1 (t), 115.8 (s), 123.7 (s), 126.0 (2×d), 127.7 (s), 128.9(2×d), 133.2 (s), 135.2 (s), 136.2 (s), 159.3 (s), 189.9 (s). Anal calcdfor C₁₉H₂₀ClNO₃: C, 65.99; H, 5.83; N, 4.05. Found: C, 66.11; H, 5.69;N, 3.91.

Ethyl3-iodo-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 7a(R¹=COOEt) with N-iodosuccinimide after 3 h at room temperature: lightyellow solid; yield: 67%; m.p.: 61-62° C.; IR: 1715 (CO), 1658 (CO)cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.24 (3H, t, J=7.0 Hz, CH₃), 1.91-2.07(2H, m, CH₂), 2.23 (3H, s, CH₃), 2.56-2.62 (4H, m, 2×CH₂), 4.24 (2H, q,J=7.0 Hz, CH₂), 5.93 (2H, s, CH₂), 6.83 (2H, d, J=8.0 Hz, H-3′ andH-5′), 7.07 (2H, d, J=8.0 Hz, H-2′ and H-6′); ¹³C nmr (DMSO-d₆) (ppm):13.8 (q), 20.6 (q), 23.2 (t), 25.3 (t), 39.3 (t), 49.3 (t), 61.2 (t),73.8 (s), 126.0 (2×d), 128.4 (s), 128.9 (2×d), 129.3 (s), 135.4 (s),136.1 (s), 139.8 (s), 159.8 (s), 189.9 (s). Anal calcd for C₁₉H₂₀INO₃:C, 52.19; H, 4.61; N, 3.20. Found: C, 52.03; H, 4.77; N, 3.14.

Method A for the Synthesis of6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylateof type 8a and7-[(dimethylamino)methylidene]-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole1-Substituted of type 8b

To a solution of 7a,b (1.3 mmol) in anhydrous DMF (2.5 mL) DMFDMA (1.73mL, 13 mmol) was added and the reaction mixture was heated at reflux for3 h. Then the reaction mixture was poured onto crushed ice and theprecipitate was filtered off and dried, in absence the solution wasextracted with ethyl acetate (3×30 mL). The organic layer was dried overNa₂SO₄ and the solvent was removed under reduced pressure. Somederivatives of type 8 are used in the next step without furtherpurification, those isolated and characterized are shown below.

Method B for the Synthesis of6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylateof Type 8a and7-[(dimethylamino)methylidene]-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole1-Substituted of Type 8b

To a solution of 7a,b (1.3 mmol) in anhydrous DMF (2.5 ml) DMFDMA (0.19mL, 1.4 mmol) was added and the reaction mixture was irradiated undermicrowave conditions (Power 50 W; Pressure (max) 100 psi; Temperature(max) 100° C.) up to completeness (TLC). Then the reaction mixture waspoured onto crushed ice and the precipitate was filtered off and dried,in absence the solution was extracted with ethyl acetate (3×30 mL). Theorganic layer was dried over Na₂SO₄ and the solvent was removed underreduced pressure.

Method C for the Synthesis of6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylateof Type 8a and7-[(dimethylamino)methylidene]-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole1-Substituted of Type 8b

To a solution of 7a,b (1.3 mmol) in anhydrous DMF (2.5 mL) DMFDMA (1.73mL, 13 mmol) was added and the reaction mixture was heated at reflux for24 h. Then the reaction mixture was poured onto crushed ice and theprecipitate was filtered off and dried, in absence the solution wasextracted with ethyl acetate (3×30 mL). The organic layer was dried overNa₂SO₄ and the solvent was removed under reduced pressure.

Method D for the Preparation of 1-Substituted6-[(dimethylamino)methylidene]-1,4,5,6-tetrahydro-7H-indole-7-ones ofType 8a and1-Substituted-7-[(dimethylamino)methylidene]-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrroleof Type 8b

To a solution of 7a-e (1.3 mmol) in anhydrous toluene (3 mL) TBDMAM(0.80 mL, 3.9 mmol) was added and the reaction mixture was heated atreflux up to completeness (TLC). After cooling, the solvent was removedunder reduced pressure.

Ethyl6-[(dimethylamino)methylidene]-1-(2-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-(2-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 7a(R¹=COOEt) with METHOD A and used in the next step without furtherpurification.

Ethyl6-[(dimethylamino)methylidene]-1-(3-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-(3-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 7a(R¹=COOEt) with METHOD A. Dark brown solid; yield: 85%; m.p.: 118-119°C.; IR: 1704 (CO), 1634 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.21 (3H, t,J=7.1 Hz, CH₃), 2.22 (3H, s, CH₃), 2.61 (2H, t, J=6.6 Hz, CH₂), 2.85(2H, t, J=6.6 Hz, CH₂), 4.17 (2H, q, J=7.1 Hz, CH₂), 3.07 (6H, s,2×CH₃), 6.11 (2H, s, CH₂), 6.65 (1H, d, J=7.5 Hz, Ar), 6.78-6.80 (2H, m,H-3 and Ar), 6.98 (1H, d, J=7.5 Hz, Ar), 7.15 (1H, t, J=7.5 Hz, Ar),7.38 (1H, s, CH); ¹³C nmr (DMSO-d₆) (ppm): 14.1 (q), 21.1 (q), 22.4 (t),24.0 (t), 43.3 (2×q), 48.1 (t), 59.9 (t), 103.5 (s), 114.7 (d), 123.0(d), 125.0 (s), 126.6 (d), 127.2 (d), 128.1 (d), 130.1 (s), 131.9 (s),137.1 (s), 139.7 (s), 149.1 (d), 160.3 (s), 178.6 (s). Anal calcd forC₂₂H₂₆N₂O₃: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.97; H, 7.29; N,7.76.

Ethyl6-[(dimethylamino)methylidene]-1-(4-chlorobenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-(4-chlorobenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 7a(R¹=COOEt) with METHOD A. Dark brown solid; yield: 78%; m.p.: 149-150°C.; IR: 1705 (CO), 1635 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.20 (3H, t,J=7.0 Hz, CH₃), 2.60 (2H, t, J=6.0 Hz, CH₂), 2.82 (2H, t, J=6.0 Hz,CH₂), 4.16 (2H, q, J=7.0 Hz, CH₂), 3.07 (6H, s, 2×CH₃), 6.09 (2H, s,CH₂), 6.79 (1H, s, H-3), 6.98 (2H, d, J=7.9 Hz, H-2′ and H-6′),7.31-7.38 (3H, s, H-3′, H-4′ and CH); ¹³C nmr (DMSO-d₆) (ppm): 14.1 (q),22.3 (t), 24.0 (t), 43.3 (2×q), 47.7 (t), 60.0 (t), 103.4 (s), 114.8(d), 124.8 (s), 128.0 (2×d), 128.1 (2×d), 130.2 (s), 131.1 (s), 131.8(s), 138.6 (s), 149.3 (d), 160.2 (s), 178.5 (s). Anal calcd forC₂₁H₂₃ClN₂O₃: C, 65.20; H, 5.99; N, 7.24. Found: C, 65.06; H, 5.85; N,7.41.

Methyl6-[(dimethylamino)methylidene]-1-(2-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-(2-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 7a(R¹=COOEt) with METHOD C. Dark brown solid; yield: 72%; m.p.: 130-131°C.; IR: 1709 (CO), 1637 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 2.33 (3H, s,CH₃), 2.64 (2H, t, J=6.2 Hz, CH₂), 2.87 (2H, t, J=6.2 Hz, CH₂), 3.05(6H, s, 2×CH₃), 3.67 (3H, s, CH₃), 5.98 (1H, d, J=7.4 Hz, Ar), 6.10 (2H,s, CH₂), 6.84 (1H, s, H-3), 6.94-7.17 (3H, m, Ar), 7.31 (1H, s, CH); ¹³Cnmr (DMSO-d₆) (ppm): 18.6 (q), 22.4 (t), 24.0 (t), 43.2 (2×q), 46.7 (t),51.3 (q), 103.4 (s), 114.6 (d), 123.1 (d), 124.8 (s), 125.9 (2×d), 129.4(d), 130.1 (s), 132.3 (s), 133.8 (s), 138.3 (s), 149.1 (d), 160.5 (s),178.4 (s). Anal calcd for C₂₁H₂₄N₂O₃: C, 71.57; H, 6.86; N, 7.95. Found:C, 71.74; H, 6.98; N, 7.78.

Methyl6-[(dimethylamino)methylidene]-1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 7a(R¹=COOEt) with METHOD C and used in the next step without furtherpurification.

Ethyl6-[(dimethylamino)methylidene]-1-[(2,4-dimethylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-(2,4-dimethylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) with METHOD A and used in the next step without furtherpurification.

Ethyl6-[(dimethylamino)methylidene]-1-[(3,4-dimethylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-(3,4-dimethylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) with METHOD A and used in the next step without furtherpurification.

Propan-2-yl6-[(dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of propan-2-yl1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 7a(R¹=COOiPr) with METHOD A and used in the next step without furtherpurification.

Ethyl7-[(dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole-2-carboxylate.This compound was obtained by reaction of ethyl1-[(4-methylphenyl)methyl]-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole-2-carboxylate7b (R¹=COOEt) with METHOD B and used in the next step without furtherpurification.

Ethyl1-[(4-bromophenyl)methyl]-6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-[(4-bromophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) with METHOD D after 16 h: light brown solid; yield: 93%;m.p.: 142-143° C.; IR: 1710 (CO), 1635 (CO) cm¹; ¹H nmr (DMSO-d₆) (ppm):1.20 (3H, t, J=7.1 Hz, CH₃), 2.60 (2H, t, J=6.7 Hz, CH₂), 2.84 (2H, t,J=6.7 Hz, CH₂), 3.06 (6H, s, 2×CH₃), 4.16 (2H, q, J=7.1 Hz, CH₂), 6.07(2H, s, CH₂), 6.78 (1H, s, H-3), 6.91 (2H, d, J=8.3 Hz, H-2′ and H-6′),7.38 (1H, s, CH), 7.45 (2H, d, J=8.3 Hz, H-3′ and H-5′); ¹³C nmr(DMSO-d₆) (ppm): 14.1 (q), 22.3 (t), 24.0 (t), 43.3 (2×q), 47.8 (t),60.0 (t), 103.4 (s), 114.9 (d), 119.6 (s), 124.8 (s), 128.4 (2×d), 130.2(s), 131.1 (2×d), 131.9 (s), 139.1 (s), 149.3 (d), 160.3 (s), 178.5 (s).Anal calcd for C₂₁H₂₃BrN₂O₃: C, 58.48; H, 5.37; N, 6.49. Found: C,58.61; H, 5.29; N, 6.33.

Ethyl6-[(dimethylamino)methylidene]-1-[(4-iodophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-[(4-iodophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) with METHOD D after 3 h: yellow solid; yield: 86%; m.p.:140-141° C.; IR: 1697 (CO), 1641 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.20(3H, t, J=7.1 Hz, CH₃), 2.60 (2H, t, J=6.7 Hz, CH₂), 2.84 (2H, t,J=5.6.7 Hz, CH₂), 3.06 (6H, s, 2×CH₃), 4.16 (2H, q, J=7.1 Hz, CH₂), 6.06(2H, s, CH₂), 6.76 (3H, d, J=9.3 Hz, H-3, H-2′ and H-6′), 7.37 (1H, s,CH), 7.62 (2H, d, J=8.2 Hz, H-3′ and H-5′); ¹³C nmr (DMSO-d₆) (ppm):14.1 (q), 22.3 (t), 23.9 (t), 43.3 (2×q), 47.9 (t), 60.0 (t), 92.4 (s),103.4 (s), 114.8 (d), 124.8 (s), 128.5 (2×d), 130.2 (s), 131.8 (s),136.9 (2×d), 139.5 (s), 149.2 (d), 160.2 (s), 178.5 (s). Anal calcd forC₂₁H₂₃IN₂O₃: C, 52.73; H, 4.85; N, 5.86. Found: C, 52.88; H, 4.99; N,5.72.

Ethyl1-(cyclopropylmethyl)-6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of1-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) with METHOD D after 2 h and used in the next step withoutfurther purification.

Ethyl6-[(dimethylamino)methylidene]-1-[(6-methylpyridin-3-yl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-[(6-methylpyridin-3-yl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) with METHOD D after 1 h: brown oil; yield: 78%; IR: 1703(CO), 1658 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.22 (3H, t, J=7.1 Hz,CH₃), 2.39 (3H, s, CH₃), 2.59 (2H, t, J=6.3 Hz, CH₂), 2.84 (2H, t, J=6.3Hz, CH₂), 3.07 (6H, s, 2×CH₃), 4.18 (2H, q, J=7.1 Hz, CH₂), 6.08 (2H, s,CH₂), 6.78 (1H, s, H-3), 7.13 (1H, d, J=8.0 Hz, H-5′), 7.25 (1H, dd,J=8.0, 2.2 Hz, H-4′), 7.40 (1H, s, CH), 8.15 (1H, d, J=2.2 Hz, H-2′);¹³C nmr (DMSO-d₆) (ppm): 14.1 (q), 22.3 (t), 23.6 (q), 24.0 (t), 43.3(2×q), 45.9 (t), 60.0 (t), 103.4 (s), 114.8 (d), 122.6 (d), 124.7 (s),130.3 (s), 131.8 (s), 131.9 (s), 134.4 (d), 147.3 (d), 149.3 (d), 156.2(s), 160.3 (s), 178.5 (s). Anal calcd for C₂₁H₂₅N₃O₃: C, 68.64; H, 6.86;N, 11.44. Found: C, 68.79; H, 7.05; N, 11.31.

Ethyl6-[(dimethylamino)methylidene]-7-oxo-1-[(2,4,6-trimethylphenyl)methyl]-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-1-[(2,4,6-trimethylphenyl)methyl]-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) with METHOD D after 3 h: brown solid; yield: 93%; m.p.:163-164° C.; IR: 1703 (CO), 1641 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.09(3H, t, J=7.0 Hz, CH₃), 1.89 (6H, s, 2×CH₃), 2.14 (3H, s, CH₃), 2.57(2H, t, J=6.4 Hz, CH₂), 2.81 (2H, t, J=6.4 Hz, CH₂), 3.05 (6H, s,2×CH₃), 4.05 (2H, q, J=7.0 Hz, CH₂), 6.05 (2H, s, CH₂), 6.68-6.72 (3H,m, H-3, H-3′ and H-5′), 7.34 (1H, s, CH); ¹³C nmr (DMSO-d₆) (ppm): 13.9(q), 19.1 (2×q), 20.2 (q), 22.5 (t), 24.1 (t), 43.3 (2×q), 45.5 (t),59.9 (t), 114.0 (d), 103.5 (s), 126.3 (s), 129.2 (2×d), 129.9 (s), 132.2(s), 132.8 (s), 134.6 (s), 135.5 (2×s), 148.9 (d), 160.5 (s), 178.8 (s).Anal calcd for C₂₄H₃₀N₂O₃: C, 73.07; H, 7.66; N, 7.10. Found: C, 72.91;H, 7.79; N, 6.97.

Ethyl6-[(dimethylamino)methylidene]-7-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl7-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) with METHOD D after 16 h: brown oil; yield: 85%; IR: 1703(CO), 1635 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.24 (3H, t, J=7.1 Hz,CH₃), 2.68 (2H, t, J=6.7 Hz, CH₂), 2.91 (2H, t, J=6.7 Hz, CH₂), 3.11(6H, s, 2×CH₃), 4.21 (2H, q, J=7.1 Hz, CH₂), 6.24 (2H, s, CH₂), 6.87(1H, s, H-3), 7.18 (2H, d, J=8.0 Hz, H-2′ and H-6′), 7.42 (1H, s, CH),7.69 (2H, d, J=8.0 Hz, H-3′ and H-5′); ¹³C nmr (DMSO-d₆) (ppm): 14.0(q), 22.3 (t), 24.0 (t), 43.2 (2×q), 48.3 (t), 60.0 (t), 103.3 (s),114.8 (d), 124.9 (s), 125.2 (2×d), 126.6 (2×d), 129.6 (s), 130.3 (s),131.9 (s), 144.5 (s), 146.9 (d, J_(C-F)=237.0 Hz), 149.2 (d), 160.2 (s),178.5 (s). Anal calcd for C₂₂H₂₃F3N₂O₃: C, 62.85; H, 5.51; N, 6.66.Found: C, 62.99; H, 5.34; N, 6.49.

Ethyl6-[(dimethylamino)methylidene]-1-[(4-fluorophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-[(4-fluorophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) with METHOD D after 5 h and used in the next step withoutfurther purification.

Ethyl6-[(dimethylamino)methylidene]-1-[3-(dimethylamino)propyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl1-[3-(dimethylamino)propyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7a (R¹=COOEt) with METHOD D after 16 h: brown oil; yield: 98%; IR: 1703(CO), 1658 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.27 (3H, t, J=7.1 Hz,CH₃), 1.72-1.83 (2H, m, CH₂), 2.11-2.33 (8H, m, 2×CH₃ and CH₂),2.50-2.58 (2H, m, CH₂), 2.73-2.82 (2H, m, CH₂), 3.07 (6H, s, 2×CH₃),2.33-3.46 (2H, m, CH₂), 4.23 (2H, q, J=7.1 Hz, CH₂), 4.68-4.76 (2H, m,CH₂), 6.66 (1H, s, H-3), 7.40 (1H, s, CH); ¹³C nmr (DMSO-d₆) (ppm): 14.2(q), 22.4 (t), 24.0 (t), 29.5 (t), 43.2 (2×q), 44.3 (t), 45.1 (2×q),56.5 (t), 59.9 (t), 103.7 (s), 113.9 (d), 124.8 (s), 129.7 (s), 131.8(s), 148.9 (d), 160.3 (s), 178.5 (s). Anal calcd for C₁₉H₂₉N₃O₃: C,65.68; H, 8.41; N, 12.09. Found: C, 65.49; H, 8.56; N, 11.97.

Propan-2-yl6-[(dimethylamino)methylidene]-1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of propan-2-yl1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7d (R¹=COOiPr) with METHOD A and used in the next step without furtherpurification.

Propan-2-yl1-(cyclopropylmethyl)-6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of propan-2-yl1-(cyclopropylmethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7d (R¹=COOiPr) with METHOD A and used in the next step without furtherpurification.

Propan-2-yl6-[(dimethylamino)methylidene]-1-[(4-fluorophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of propan-2-yl1-[(4-fluorophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7d (R¹=COOiPr) with METHOD A and used in the next step without furtherpurification.

6-[(Dimethylamino)methylidene]-1-[(3-methylphenyl)methyl]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction of1-[(3-methylphenyl)methyl]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide7e (R¹=CONHR⁴) with METHOD D after 6 h and used in the next step withoutfurther purification.

N-cyclopropyl-6-[(dimethylamino)methylidene]-1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction ofN-cyclopropyl-1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide7e (R¹=CONHR⁴) with METHOD D after 4 h: brown solid; yield: 99%; m.p.:156-157° C.; IR: 3433 (NH), 1664 (CO), 1635 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 0.47-0.64 (4H, m, 2×CH₂), 2.21 (3H, s, CH₃), 2.68-2.82 (4H, m,2×CH₂), 3.38 (1H, s, CH), 3.04 (6H, s, 2×CH₃), 6.09 (2H, s, CH₂), 6.54(1H, s, H-3), 6.74-7.10 (4H, m, H-2′, H-4′, H-5′ and H-6′), 7.31 (1H, s,CH), 8.28 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 5.7 (2×t), 21.1 (q),22.5 (d), 22.6 (t), 24.2 (t), 43.2 (2×q), 47.5 (t), 103.4 (s), 110.1(d), 123.6 (d), 127.1 (2×d), 128.0 (d), 129.6 (s), 129.9 (s), 130.2 (s),136.9 (s), 140.1 (s), 148.2 (d), 162.5 (s), 178.6 (s). Anal calcd forC₂₃H₂₇N₃O₂: C, 73.18; H, 7.21; N, 11.13. Found: C, 73.07; H, 7.36; N,11.27.

6-[(Dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction of1-[(4-methylphenyl)methyl]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide7e (R¹=CONHR⁴) with METHOD D after 16 h: brown solid; yield: 99%; m.p.:176-177° C.; IR: 3428 (NH), 1658 (CO), 1635 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.08 (6H, d, J=6.5 Hz, 2×CH₃), 2.21 (3H, s, CH₃), 2.55 (2H, t,J=6.7 Hz, CH₂), 2.82 (2H, t, J=6.7 Hz, CH₂), 3.04 (6H, s, 2×CH₃),3.93-4.06 (1H, m, CH), 6.06 (2H, s, CH₂), 6.53 (1H, s, H-3), 6.93 (2H,d, J=7.8 Hz, H-3′ and H-5′), 7.02 (2H, d, J=7.8 Hz, H-2′ and H-6′), 7.33(1H, s, CH), 8.06 (1H, d, J=7.7 Hz, NH); ¹³C nmr (DMSO-d₆) (ppm): 20.6(q), 22.2 (2×q), 22.6 (t), 24.2 (t), 40.3 (d), 43.2 (2×q), 47.1 (t),103.4 (s), 110.0 (d), 126.8 (2×d), 128.6 (2×d), 129.3 (s), 130.3 (s),130.5 (s), 135.6 (s), 137.1 (s), 148.2 (d), 160.5 (s), 178.6 (s). Analcalcd for C₂₃H₂₉N₃O₂: C, 72.79; H, 7.70; N, 11.07. Found: C, 72.87; H,7.59; N, 10.94.

N-cyclopropyl-6-[(dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction ofN-cyclopropyl-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide7e (R¹=CONHR⁴) with METHOD D after 8 h: brown solid; yield: 78%; p.f.:97-98° C.; IR: 3428 (NH), 1758 (CO), 1635 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 0.40-0.48 (2H, m, CH₂), 0.62-0.70 (2H, m, CH₂), 2.22 (3H, s,CH₃), 2.55 (2H, t, J=6.7 Hz, CH₂), 2.70-2.89 (3H, m, CH₂ e CH), 3.04(6H, s, 2×CH₃), 5.77 (2H, s, CH₂), 6.52 (1H, s, H-3), 6.91 (2H, d, J=7.9Hz, H-3′ e H-5′), 7.03 (2H, d, J=7.9 Hz, H-2′ e H-6′), 7.33 (1H, s, CH),8.24 (1H, d, J=4.0 Hz, NH); ¹³C nmr (DMSO-d₆) (ppm): 5.7 (2×t), 20.6(q), 22.5 (d), 22.6 (t), 24.2 (t), 43.2 (2×q), 47.2 (t), 103.4 (s),110.1 (d), 126.7 (2×d), 128.6 (2×d), 129.6 (s), 129.9 (s), 130.3 (s),135.6 (s), 137.2 (s), 148.2 (d), 162.5 (s), 178.6 (s). Anal calcd forC₂₃H₂₇N₃O₂: C, 73.18; H, 7.21; N, 11.13. Found: C, 73.22; H, 7.09; N,11.02.

1-[(4-Bromophenyl)methyl]-6-[(dimethylamino)methylidene]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction of1-[(4-bromophenyl)methyl]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamide7e (R¹=CONHR⁴) with METHOD D after 8 h: light brown solid; yield: 99%;m.p.: 212-213° C.; IR: 3433 (NH), 1658 (CO), 1635 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.07 (6H, d, J=6.4 Hz, 2×CH₃), 2.57 (2H, t, J=5.8 Hz,CH₂), 2.83 (2H, t, J=5.8 Hz, CH₂), 3.04 (6H, s, 2×CH₃), 3.87-4.09 (1H,m, CH), 6.06 (2H, s, CH₂), 6.60 (1H, s, H-3), 6.98 (2H, d, J=8.0 Hz,H-2′ and H-6′), 7.32 (1H, s, CH), 7.43 (2H, d, J=8.0 Hz, H-3′ and H-5′),8.07 (1H, d, J=7.7 Hz, NH); ¹³C nmr (DMSO-d₆) (ppm): 22.2 (2×q), 22.6(t), 24.1 (t), 40.4 (d), 43.2 (2×q), 47.2 (t), 103.3 (s), 110.1 (d),119.6 (s), 129.0 (2×d), 129.4 (s), 130.1 (s), 130.4 (s), 130.9 (2×d),139.6 (s), 148.3 (d), 160.3 (s), 178.5 (s). Anal calcd for C₂₂H₂₆BrN₃O₂:C, 59.46; H, 5.90; N, 9.46. Found: C, C, 59.59; H, 6.11; N, 9.32.

1-[(4-Bromophenyl)methyl]-N-cyclopropyl-6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide.This compound was obtained by reaction of1-[(4-bromophenyl)methyl]-N-cyclopropyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamide7e (R¹=CONHR⁴) with METHOD D after 8 h: light brown solid; yield: 99%;m.p.: 191-192° C.; IR: 3433 (NH), 1653 (CO), 1635 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 0.50-0.65 (4H, m, 2×CH₂), 2.57 (2H, t, J=6.3 Hz, CH₂),2.73-2-83 (3H, m, CH₂ and CH), 3.04 (6H, s, 2×CH₃), 6.08 (2H, s, CH₂),6.62 (1H, s, H-3), 6.97 (2H, d, J=7.3 Hz, H-2′ and H-6′), 7.32 (1H, s,CH), 7.45 (2H, d, J=8.3 Hz, H-3′ and H-5′), 8.29 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 6.2 (2×t), 23.0 (d), 23.1 (t), 24.6 (t), 43.7 (2×q),47.8 (t), 103.9 (s), 110.8 (d), 120.0 (s), 129.4 (2×d), 130.0 (s), 130.1(s), 130.9 (s), 131.4 (2×d), 140.1 (s), 148.8 (d), 162.8 (s), 179.0 (s).Anal calcd for C₂₂H₂₄BrN₃O₂: C, 59.73; H, 5.47; N, 9.50. Found: C,59.87; H, 5.65; N, 9.39.

Ethyl3-chloro-6-[(dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl3-chloro-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7f (R¹=COOEt) with METHOD D after 4 h: brown oil; yield: 80%; IR: 3377(NH), 1702 (CO), 1666 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.21 (3H, t,J=7.1 Hz, CH₃), 2.23 (3H, s, CH₃), 2.54 (2H, t, J=6.9 Hz, CH₂), 2.88(2H, t, J=6.9 Hz, CH₂), 3.09 (6H, s, 2×CH₃), 4.20 (2H, q, J=7.1 Hz,CH₂), 6.09 (2H, s, CH₂), 6.84 (2H, d, J=7.9 Hz, H-3′ and H-5′), 7.06(2H, d, J=7.9 Hz, H-2′ and H-6′), 7.43 (1H, s, CH); ¹³C nmr (DMSO-d₆)(ppm): 13.9 (q), 20.1 (t), 20.6 (q), 23.2 (t), 43.4 (2×q), 48.3 (t),60.5 (t), 102.8 (s), 115.7 (s), 121.4 (s), 126.1 (2×d), 128.2 (s), 128.8(2×d), 130.1 (s), 135.9 (s), 136.1 (s), 150.0 (d), 159.5 (s), 177.8 (s).Anal calcd for C₂₂H₂₅ClN₂O₃: C, 65.91; H, 6.29; N, 6.99. Found: C,65.79; H, 6.44; N, 7.08.

Ethyl6-[(dimethylamino)methylidene]-3-iodo-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate.This compound was obtained by reaction of ethyl3-iodo-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate7f (R¹=COOEt) with METHOD D after 16 h: brown solid; resa: 66%; m.p.:131-132° C.; IR: 3416 (NH), 1703 (CO), 1641 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.25 (3H, t, J=7.1 Hz, CH₃), 2.22 (3H, s, CH₃), 2.47 (2H, t,J=6.7 Hz, CH₂), 2.87 (2H, t, J=6.7 Hz, CH₂), 3.08 (6H, s, 2×CH₃), 4.20(2H, q, J=7.1 Hz, CH₂), 6.10 (2H, s, CH₂), 6.83 (2H, d, J=8.0 Hz, H-3′and H-5′), 7.05 (2H, d, J=8.0 Hz, H-2′ and H-6′), 7.42 (1H, s, CH); ¹³Cnmr (DMSO-d₆) (ppm): 13.9 (q), 20.6 (q), 23.3 (t), 24.3 (t), 43.3 (2×q),48.7 (t), 60.6 (t), 77.7 (s), 102.7 (s), 126.0 (s), 126.1 (2×d), 128.8(2×d), 131.6 (s), 134.8 (s), 135.9 (s), 136.3 (s), 149.8 (d), 159.9 (s),178.0 (s). Anal calcd for C₂₂H₂₅IN₂O₃: C, 53.67; H, 5.12; N, 5.69.Found: C, 53.80; H, 5.01; N, 5.55.

General Procedure for the Synthesis of4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinolinones and1,4,5,6,9,10-hexahydropyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridinones ofType 9

To a suspension of 8 (4 mmol) in anhydrous ethanol (50 mL), a solutionof the proper cyanomethylene compound of type R³SO₂CH₂CN (6 mmol) inanhydrous ethanol (60 mL) was added dropwise under nitrogen atmosphere.Then the reaction mixture was heated at reflux for 24 h. After cooling,the solvent was removed under reduced pressure and the crude was addedof a mixture of anhydrous toluene/acetic acid (1:1) and the reactionmixture was heated at reflux for 24 h with the Dean-Stark apparatus toremove water azeotropically and to facilitate the cyclization of thepyridine ring. After cooling, the solid was filtered off andrecrystallized from ethanol or purified by chromatography SEPACORE BÜCHI(DCM/AcOEt 9:1).

Ethyl1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP015). This product was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-(2-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonylacetonitrile after 24 h at reflux. The crude waspurified by chromatography. Dark yellow solid; yield: 62%; m.p.: 97-98°C.; IR: 3399 (NH), 1703 (CO), 1663 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):1.22 (3H, t, J=7.1 Hz, CH₃), 2.17 (3H, s, CH₃), 2.70 (2H, t, J=6.5 Hz,CH₂), 2.86 (2H, t, J=6.5 Hz, CH₂), 4.17 (2H, q, J=7.1 Hz, CH₂), 6.37(2H, s, CH₂), 6.77-7.08 (5H, m, H-3′, H-4′, H-5′, H-6′ and H-7),7.56-7.69 (3H, m, H-3″, H-4″ and H-5″), 7.93 (2H, d, J=7.3 Hz, H-2″ eH-6″), 8.13 (1H, s, H-4), 11.91 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):14.1 (q), 20.5 (q), 20.8 (t), 27.2 (t), 48.1 (t), 59.9 (t), 115.8 (d),117.2 (s), 125.9 (2×d), 127.5 (2×d), 127.9 (s), 128.8 (2×d), 129.0(2×d), 129.5 (d), 133.4 (d), 135.8 (s), 136.4 (s), 137.5 (s), 138.2 (s),140.6 (s), 149.8 (s), 151.1 (s), 157.9 (s), 160.3 (s). Anal calcd forC₂₈H₂₆N₂O₅S: C, 66.91; H, 5.21; N, 5.57. Found: C, 66.84; H, 5.09; N,5.76.

Ethyl1-(3-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP016). This product was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-(3-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonylacetonitrile after 24 h at reflux. The crude waspurified by chromatography. Dark yellow solid; yield: 64%; m.p.:160-161° C.; IR: 3405 (NH), 1721 (CO), 1652 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.21 (3H, t, J=7.1 Hz, CH₃), 2.14 (3H, s, CH₃), 2.71 (2H, t,J=7.1 Hz, CH₂), 2.86 (2H, t, J=7.1 Hz, CH₂), 4.17 (2H, q, J=7.1 Hz,CH₂), 6.38 (2H, s, CH₂), 6.59 (1H, d, J=7.1 Hz, Ar), 6.77 (1H, s, H-7),6.88-6.94 (2H, m, Ar), 7.05 (1H, t, J=7.5 Hz, Ar), 7.56-7.72 (3H, m,H-3″, H-4″ and H-5″), 7.93 (2H, d, J=7.5 Hz, H-2″ and H-6″), 8.13 (1H,s, H-4), 11.94 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.1 (q), 20.8 (q),21.0 (t), 27.2 (t), 48.3 (t), 59.9 (t), 115.9 (d), 117.2 (s), 118.4 (s),122.8 (d), 124.1 (s), 125.5 (s), 126.6 (d), 127.3 (d), 127.5 (s), 127.8(2×d), 128.2 (d), 129.0 (2×d), 130.9 (s), 133.4 (d), 137.2 (s), 138.1(d), 139.4 (s), 140.6 (s), 157.9 (s), 160.1 (s). Anal calcd forC₂₈H₂₆N₂O₅S: C, 66.91; H, 5.21; N, 5.57. Found: C, 67.09; H, 5.07; N,5.69.

Ethyl1-(4-chlorobenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP017). This product was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-(4-chlorobenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonylacetonitrile after 24 h at reflux. The crude waspurified by chromatography. Dark yellow solid; yield: 65%; m.p.:101-102° C.; IR: 3342 (NH), 1701 (CO), 1663 (CO) cm⁻¹; ¹H nmr (CDCl₃)(ppm): 1.30 (3H, t, J=7.1 Hz, CH₃), 2.34 (3H, s, CH₃), 2.75-3.04 (4H, m,2×CH₂), 4.25 (2H, q, J=7.1 Hz, CH₂), 6.15 (2H, s, CH₂), 6.89-7.01 (3H,m, Ar), 7.21-7.37 (2H, m, Ar), 7.48-7.64 (3H, m, H-3″, H-4″ and H-5″),7.98-8.09 (4H, m, H-2″, H-6″, H-4 and NH); ¹³C nmr (CDCl₃) (ppm): 14.2(q), 21.5 (t), 27.8 (t), 49.1 (t), 53.4 (t), 116.0 (d), 118.5 (s), 127.0(s), 127.1 (s), 127.7 (2×d), 127.8 (2×d), 128.6 (s), 128.9 (2×d), 129.2(2×d), 129.7 (d), 133.1 (s), 133.7 (d), 136.8 (s), 140.7 (s), 148.3 (s),152.3 (s), 157.3 (s), 160.6 (s). Anal calcd for C₂₇H₂₃ClN₂O₅S: C, 62.01;H, 4.43; N, 5.36. Found: C, 61.92; H, 4.66; N, 5.19.

Ethyl7-[(4-chlorophenyl)sulfonyl]-1-(4-methylbenzyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP018). This product was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith 4-chlorophenylsulfonyl acetonitrile after 24 h at reflux. The crudewas purified by chromatography. Dark yellow solid; yield: 58%; m.p.:196-197° C.; IR: 3285 (NH), 1712 (CO), 1671 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.14 (3H, t, J=7.0 Hz, CH₃), 2.34 (3H, s, CH₃), 2.55 (2H, t,J=6.9 Hz, CH₂), 2.92 (2H, t, J=6.9 Hz, CH₂), 4.08 (2H, q, J=7.0 Hz,CH₂), 6.37 (2H, s, CH₂), 6.87-7.13 (4H, m, H-2′, H-3′, H-4′ and H-5′),7.66 (2H, d, J=8.4 Hz, H-3″ and H-4″), 7.91 (2H, d, J=8.4 Hz, H-2″ andH-6″), 8.07 (1H, s, H-7), 8.15 (1H, s, H-4), 12.02 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 14.0 (q), 18.7 (q), 20.8 (t), 27.3 (t), 47.1 (t), 59.8(t), 103.6 (s), 115.9 (s), 116.0 (d), 122.5 (d), 125.6 (s), 126.0 (2×d),127.5 (s), 129.1 (2×d), 129.5 (2×d), 129.9 (2×d), 131.1 (s), 131.2 (s),134.2 (s), 138.3 (s), 138.4 (s), 139.3 (s), 157.8 (s), 159.8 (s). Analcalcd for C₂₈H₂₅ClN₂O₅S: C, 62.62; H, 4.33; N, 5.22. Found: C, 62.77; H,4.25; N, 5.08.

Ethyl7-(benzenesulfonyl)-1-[(2,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP021). This product was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-[(2,4-dimethylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatecon phenylsulfonylacetonitrile after 24 h at reflux. The crude waspurified by chromatography. Dark yellow solid; yield: 64%; m.p.:182-183° C.; IR: 3319 (NH), 1699 (CO), 1640 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.20 (3H, t, J=7.1 Hz, CH₃), 1.97 (3H, s, CH₃), 2.18 (3H, s,CH₃), 2.79 (2H, t, J=7.1 Hz, CH₂), 2.99 (2H, t, J=7.1 Hz, CH₂), 4.14(2H, q, J=7.1 Hz, CH₂), 5.80 (1H, d, J=7.7 Hz, Ar), 6.38 (2H, s, CH₂),6.75 (1H, d, J=7.7 Hz, Ar), 6.96-6.98 (2H, m, Ar and H-7), 7.59-7.76(3H, m, H-3″, H-4″ and H-5″), 7.97 (2H, d, J=6.7 Hz, H-2″ and H-6″),8.20 (1H, s, H-4), 11.94 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.0 (q),18.5 (q), 20.4 (q), 20.8 (t), 27.3 (t), 47.0 (t), 59.8 (t), 115.9 (d),117.4 (s), 122.6 (d), 124.2 (s), 125.5 (s), 126.5 (d), 127.3 (s), 127.9(2×d), 129.0 (2×d), 130.3 (d), 131.3 (s), 133.4 (d), 133.9 (s), 134.9(s), 135.3 (s), 138.0 (d), 140.6 (s), 156.1 (s), 157.8 (s), 159.8 (s).Anal calcd for C₂₉H₂₈N₂O₅S: C, 67.42; H, 5.46; N, 5.42. Found: C, 67.31;H, 5.60; N, 5.33.

Ethyl7-(benzenesulfonyl)-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP025). This product was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-[(3,4-dimethylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatecon phenylsulfonylacetonitrile after 24 h at reflux. The crude waspurified by chromatography. Dark yellow solid; yield: 65%; m.p.: 90-91°C.; IR: 3296 (NH), 1703 (CO), 1639 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):1.22 (3H, t, J=7.1 Hz, CH₃), 2.04 (3H, s, CH₃), 2.07 (3H, s, CH₃), 2.69(2H, t, J=7.1 Hz, CH₂), 2.85 (2H, t, J=7.1 Hz, CH₂), 4.18 (2H, q, J=7.1Hz, CH₂), 6.34 (2H, s, CH₂), 6.52 (1H, d, J=7.8 Hz, Ar), 6.73 (1H, s,Ar), 6.87-6.93 (2H, m, Ar and H-7), 7.56-7.70 (3H, m, H-3″, H-4″ andH-5″), 7.93 (2H, d, J=6.8 Hz, H-2″ and H-6″), 8.13 (1H, s, H-4), 11.90(1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.1 (q), 18.9 (q), 19.5 (q), 20.8(t), 27.2 (t), 48.0 (t), 59.9 (t), 115.9 (d), 123.2 (d), 125.4 (s),127.3 (d), 127.5 (s), 127.8 (2×d), 129.0 (2×d), 129.4 (d), 130.8 (s),133.4 (d), 134.5 (s), 135.8 (s), 137.9 (d), 140.6 (s), 142.0 (s), 150.7(s), 151.5 (s), 157.0 (s), 157.8 (s), 160.1 (s). Anal calcd forC₂₉H₂₈N₂O₅S: C, 67.42; H, 5.46; N, 5.42. Found: C, 67.59; H, 5.57; N,5.29.

Propan-2-yl7-(benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP022). This product was obtained by reaction of propan-2-yl6-[(dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatecon phenylsulfonylacetonitrile after 24 h at reflux. The crude waspurified by chromatography. Dark yellow solid; yield: 58%; m.p.: 97-98°C.; IR: 3399 (NH), 1700 (CO), 1664 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):1.19 (3H, s, CH₃), 1.22 (3H, s, CH₃), 2.16 (3H, s, CH₃), 2.69 (2H, t,J=7.2 Hz, CH₂), 2.85 (2H, t, J=7.2 Hz, CH₂), 4.93-5.05 (1H, m, CH), 6.36(2H, s, CH₂), 6.76-6.84 (3H, m, H-2′, H-6′ and H-7), 6.98 (2H, d, J=7.8Hz, H-3′ and H-5′), 7.55-7.72 (3H, m, H-3″, H-4″ and H-5″), 7.93 (2H, d,J=7.8 Hz, H-2″ and H-6″), 8.11 (1H, s, H-4), 11.95 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 20.5 (q), 20.8 (t), 21.6 (2×q), 27.2 (t), 48.1 (t),67.3 (d), 116.0 (d), 117.2 (s), 124.1 (s), 125.9 (2×d), 127.8 (2×d),127.5 (s), 128.8 (2×d), 129.0 (2×d), 130.7 (s), 133.4 (d), 135.7 (s),136.4 (s), 138.0 (d), 140.6 (s), 146.2 (s), 150.6 (s), 157.9 (s), 159.7(s). Anal calcd for C₂₉H₂₈N₂O₅S: C, 67.42; H, 5.46; N, 5.42. Found: C,67.29; H, 5.58; N, 5.55.

Ethyl7-(4-methylbenzene-1-sulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP023). This product was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatecon 4-toluensulfonylacetonitrile after 24 h at reflux. The crude waspurified by chromatography. Dark yellow solid; yield: 65%; m.p.:289-290° C.; IR: 3329 (NH), 1723 (CO), 1654 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.22 (3H, t, J=7.1 Hz, CH₃), 2.17 (3H, s, CH₃), 2.37 (3H, s,CH₃), 2.69 (2H, t, J=7.6 Hz, CH₂), 2.89 (2H, t, J=7.6 Hz, CH₂), 4.17(2H, q, J=7.1 Hz, CH₂), 6.38 (2H, s, CH₂), 6.78 (2H, d, J=7.8 Hz, Ar),6.87 (1H, s, H-7), 6.98 (2H, d, J=7.8 Hz, Ar), 7.39 (2H, d, J=8.0 Hz,Ar), 7.80 (2H, d, J=8.0 Hz, Ar), 8.07 (1H, s, H-4), 11.86 (1H, s, NH);¹³C nmr (DMSO-d₆) (ppm): 14.1 (q), 20.5 (q), 20.8 (t), 21.0 (q), 27.2(t), 48.0 (t), 59.9 (t), 115.9 (d), 117.5 (s), 125.4 (s), 125.9 (2×d),127.4 (s), 127.9 (2×d), 128.8 (2×d), 129.6 (2×d), 130.7 (s), 133.5 (s),135.7 (s), 136.4 (s), 137.8 (d), 144.0 (s), 150.4 (s), 157.8 (s), 160.1(s), 164.7 (s). Anal calcd for C₂₉H₂₈N₂O₅S: C, 67.42; H, 5.46; N, 5.42.Found: C, 67.55; H, 5.39; N, 5.60.

Ethyl7-(metansulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP024). This product was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatecon methylsulfonylacetonitrile after 24 h at reflux. The crude waspurified by chromatography. Dark yellow solid; yield: 60%; m.p.:189-190° C.; IR: 3307 (NH), 1703 (CO), 1660 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.24 (3H, t, J=7.1 Hz, CH₃), 2.19 (3H, s, CH₃), 2.69 (2H, t,J=7.2 Hz, CH₂), 2.86 (2H, t, J=7.2 Hz, CH₂), 3.24 (3H, s, CH₃), 4.19(2H, q, J=7.1 Hz, CH₂), 6.46 (2H, s, CH₂), 6.83-7.05 (5H, m, Ar andH-7), 7.92 (1H, s, H-4), 12.20 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):14.6 (q), 21.0 (q), 21.4 (t), 27.7 (t), 42.4 (q), 49.4 (t), 59.9 (t),116.4 (d), 117.3 (s), 125.4 (s), 126.6 (2×d), 127.8 (s), 128.8 (s),129.4 (2×d), 136.3 (s), 136.9 (d), 155.1 (s), 156.9 (s), 158.5 (s),160.7 (s), 161.1 (s). Anal calcd for C₂₃H₂₄N₂O₅S: C, 62.71; H, 5.49; N,6.36. Found: C, 62.62; H, 5.31; N, 6.58.

Methyl1-(4-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP019). This product was obtained by reaction of methyl6-[(dimethylamino)methylidene]-1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatecon phenylsulfonylacetonitrile after 24 h at reflux. The crude waspurified by chromatography. Dark yellow solid; yield: 50%; m.p.: >400°C.; IR: 3390 (NH), 1703 (CO), 1680 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):1.27 (3H, t, J=7.1 Hz, CH₃), 2.17 (3H, s, CH₃), 2.66-2.73 (2H, m, CH₂),2.85-2.92 (2H, m, CH₂), 3.71 (3H, s, CH₃), 6.38 (2H, s, CH₂), 6.79 (2H,d, J=7.9 Hz, H-3′ and H-5′), 6.87 (1H, m, H-7), 6.98 (2H, d, J=8.5 Hz,H-2′ and H-6′), 7.55-7.75 (3H, m, H-3″, H-4″ and H-5″), 7.93 (2H, d,J=6.8 Hz, H-2″ and H-6″), 8.07 (1H, s, H-4), 11.95 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 20.6 (q), 22.0 (t), 25.0 (t), 48.1 (t), 57.8 (q), 102.8(s), 108.7 (s), 117.4 (d), 125.9 (s), 127.8 (2×d), 128.7 (2×d), 128.8(2×d), 129.0 (2×d), 130.0 (s), 131.5 (s), 131.7 (s), 133.9 (d), 136.3(d), 136.4 (s), 155.1 (s), 157.1 (s), 161.1 (s), 163.3 (s). Anal calcdfor C₂₇H₂₄N₂O₅S: C, 66.38; H, 4.95; N, 5.73. Found: C, 66.25; H, 5.08;N, 5.61.

Methyl1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP020). This product was obtained by reaction of methyl6-[(dimethylamino)methylidene]-1-(2-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatecon phenylsulfonylacetonitrile after 24 h at reflux. The crude waspurified by chromatography. Dark yellow solid; yield: 66%; m.p.:158-159° C.; IR: 3502 (NH), 1711 (CO), 1669 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 2.35 (3H, s, CH₃), 2.75 (2H, t, J=6.7 Hz, CH₂), 2.96 (2H, t,J=6.7 Hz, CH₂), 3.64 (3H, s, CH₃), 6.38 (2H, s, CH₂), 6.90-7.12 (4H, m,Ar), 7.54-7.72 (3H, m, H-3″, H-4″ and H-5″), 7.91 (2H, d, J=7.0 Hz, H-2″and H-6″), 8.07 (1H, s, H-7), 8.15 (1H, s, H-4), 11.92 (1H, s, NH); ¹³Cnmr (DMSO-d₆) (ppm): 18.8 (q), 20.9 (t), 27.3 (t), 47.1 (t), 51.3 (q),116.0 (d), 117.6 (s), 122.6 (d), 125.1 (s), 126.0 (s), 127.4 (s), 127.9(2×d), 128.7 (d), 129.0 (2×d), 129.5 (d), 131.4 (s), 131.7 (d), 133.5(d), 134.2 (s), 138.3 (s), 140.5 (s), 150.6 (s), 157.8 (s), 160.2 (s).Anal calcd for C₂₇H₂₄N₂O₅S: C, 66.38; H, 4.95; N, 5.73. Found: C, 66.26;H, 5.07; N, 5.63.

Ethyl8-(benzenesulfonyl)-1-[(4-methylphenyl)methyl]-9-oxo-1,4,5,6,9,10-hexahydropyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridine-2-carboxylate(PP048). This product was obtained by reaction of ethyl7-[(dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrolo-2-carboxylatecon phenylsulfonylacetonitrile after 24 h at reflux. The crude waspurified by chromatography. Dark yellow solid; yield: 50%; m.p.:101-102° C.; IR: 3416 (NH), 1714 (CO), 1667 (CO) cm⁻¹; ¹H nmr (CDCl₃)(ppm): 1.25 (3H, t, J=7.1 Hz, CH₃), 2.05-2.46 (7H, m, 2×CH₂ and CH₃),2.89-2.66 (2H, m, CH₂), 4.21 (2H, q, J=7.1 Hz, CH₂), 5.75 (2H, s, CH₂),6.69-7.56 (6H, m, Ar), 8.02-8.28 (4H, m, Ar and H-7), 11.13 (1H, s, NH);¹³C nmr (CDCl₃) (ppm): 14.2 (q), 21.1 (q), 29.7 (t), 31.5 (t), 36.6 (t),53.4 (t), 60.4 (t), 125.6 (d), 125.9 (s), 126.5 (s), 128.6 (2×d), 128.9(2×d), 129.1 (s), 129.5 (2×d), 129.8 (2×d), 133.8 (s), 134.9 (s), 136.2(s), 137.4 (s), 145.9 (d), 160.6 (s), 162.7 (s), 165.1 (s), 171.5 (s).Anal calcd for C₂₉H₂₈N₂O₅S: C, 67.42; H, 5.46; N, 5.42. Found: C, 67.68;H, 5.33; N, 5.58.

Ethyl7-(benzenesulfonyl)-1-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP060). This compound was obtained by reaction of ethyl1-[(4-bromophenyl)methyl]-6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Brown solid; yield: 65%; m.p.: 226-227°C.; IR: 3405 (NH), 1732 (CO), 1720 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):1.21 (3H, t, J=7.1 Hz, CH₃), 2.71 (2H, t, J=7.2 Hz, CH₂), 2.91 (2H, t,J=7.2 Hz, CH₂), 4.16 (2H, q, J=7.1 Hz, CH₂), 6.37 (2H, s, CH₂),6.84-6.89 (3H, m, H-3, H-2′ and H-6′), 7.39 (2H, d, J=8.3 Hz, H-3′ andH-5′), 7.56-7.72 (3H, m, H-3″, H-4″ and H-5″), 7.93 (2H, d, J=7.2 Hz,H-2″ and H-6″), 8.14 (1H, s, H-6), 11.93 (1H, s, NH); ¹³C nmr (DMSO-d₆)(ppm): 14.1 (q), 20.8 (t), 27.1 (t), 48.0 (t), 60.0 (t), 116.0 (d),117.2 (s), 119.7 (s), 124.1 (s), 125.3 (s), 127.5 (s), 127.9 (2×d),128.2 (2×d), 129.0 (2×d), 130.6 (s), 131.1 (2×d), 133.4 (d), 138.0 (d),138.8 (s), 140.6 (s), 150.4 (s), 157.9 (s), 160.0 (s). Anal calcd forC₂₇H₂₃BrN₂O₅S: C, 57.15; H, 4.09; N, 4.94. Found: C, 57.12; H, 3.94; N,5.08.

Ethyl7-(benzenesulfonyl)-1-[(4-iodophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP062). This compound was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-[(4-iodophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Yellow solid; yield: 55%; m.p.: 189-190°C.; IR: 3324 (NH), 3399 (NH), 1700 (CO), 1696 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.21 (3H, t, J=6.7 Hz, CH₃), 2.71 (2H, t, J=6.8 Hz,CH₂), 2.91 (2H, t, J=6.8 Hz, CH₂), 4.16 (2H, q, J=6.7 Hz, CH₂), 6.35(2H, s, CH₂), 6.71 (2H, d, J=7.5 Hz, H-2′ and H-6′), 6.89 (1H, s, H-3),7.54-7.64 (3H, m, H-3′, H-5′, H-3″, H-4″ and H-5″), 7.93 (2H, d, J=6.8Hz, H-2″ and H-6″), 8.14 (1H, s, H-6), 11.92 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 14.1 (q), 20.8 (t), 27.1 (t), 48.1 (t), 60.0 (t), 92.5(s), 111.1 (s), 116.0 (d), 117.3 (s), 119.1 (s), 124.2 (s), 125.3 (s),127.5 (s), 127.9 (2×d), 128.4 (2×d), 129.0 (2×d), 130.6 (s), 133.4 (d),137.0 (2×d), 139.2 (d), 140.6 (s), 157.9 (s), 160.0 (s). Anal calcd forC₂₇H₂₃IN₂O₅S: C, 52.78; H, 3.77; N, 4.56. Found: C, 52.90; H, 3.65; N,4.69.

Ethyl7-(benzenesulfonyl)-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP064). This compound was obtained by reaction of(1-(cyclopropylmethyl)-6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Yellow solid; yield: 55%; m.p.: 195-196°C.; IR: 3416 (NH), 1751 (CO), 1716 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):0.24-0.28 (4H, m, 2×CH₂), 1.13-1.30 (4H, m, CH₃ and CH), 2.66 (2H, t,J=7.2 Hz, CH₂), 2.90 (2H, t, J=7.2 Hz, CH₂), 4.22 (2H, q, J=7.0 Hz,CH₂), 5.04 (2H, d, J=6.3 Hz, CH₂), 6.80 (1H, s, H-3), 7.57-7.70 (3H, m,H-3″, H-4″ and H-5″), 7.95 (2H, d, J=7.0 Hz, H-2″ and H-6″), 8.15 (1H,s, H-6), 11.87 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 3.1 (2×t), 13.3(d), 14.2 (q), 20.8 (t), 27.3 (t), 48.6 (t), 59.9 (t), 115.5 (d), 117.1(s), 124.0 (s), 125.0 (s), 127.2 (s), 127.9 (2×d), 129.0 (2×d), 130.3(s), 133.4 (d), 138.0 (d), 140.7 (s), 150.8 (s), 157.8 (s), 160.4 (s).Anal calcd for C₂₄H₂₄N₂O₅S: C, 63.70; H, 5.35; N, 6.19. Found: C, 63.59;H, 5.23; N, 6.32.

Ethyl7-(benzenesulfonyl)-1-[(6-methylpyridin-3-yl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP066). This compound was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-[(6-methylpyridin-3-yl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Light yellow solid; yield: 57%; m.p.:290-291° C.; IR: 3393 (NH), 1700 (CO), 1692 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.23 (3H, t, J=7.1 Hz, CH₃), 2.34 (3H, s, CH₃), 2.71 (2H, t,J=7.4 Hz, CH₂), 2.91 (2H, t, J=7.4 Hz, CH₂), 4.19 (2H, q, J=7.1 Hz,CH₂), 6.37 (2H, s, CH₂), 6.89 (1H, s, H-3), 7.05-7.18 (2H, m, H-4′ andH-5′), 7.57-7.74 (3H, m, H-3″, H-4″ and H-5″), 7.94 (2H, d, J=6.8 Hz,H-2″ and H-6″), 8.12-8.15 (2H, m, H-6 and H-2′), 11.96 (1H, s, NH); ¹³Cnmr (DMSO-d₆) (ppm): 14.1 (q), 20.8 (t), 23.5 (q), 27.1 (t), 46.1 (t),60.0 (t), 116.0 (d), 122.5 (s), 122.7 (d), 125.5 (s), 126.3 (s), 127.9(2×d), 128.4 (s), 129.0 (2×d), 131.9 (s), 133.4 (d), 134.2 (d), 138.1(d), 139.5 (s), 140.2 (s), 143.1 (s), 147.1 (d), 156.4 (s), 159.1 (s),162.7 (s). Anal calcd for C₂₇H₂₅N₃O₅S: C, 64.40; H, 5.00; N, 8.34.Found: C, 64.28; H, 5.19; N, 8.47.

Ethyl7-(benzenesulfonyl)-8-oxo-1-[(2,4,6-trimethylphenyl)methyl]-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP068). This compound was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-7-oxo-1-[(2,4,6-trimethylphenyl)methyl]-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Brown solid; yield: 66%; m.p.: 156-157°C.; IR: 3405 (NH), 1703 (CO), 1641 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):1.02 (3H, t, J=7.1 Hz, CH₃), 1.87 (6H, s, 2×CH₃), 2.12 (3H, s, CH₃),2.72 (2H, t, J=5.7 Hz, CH₂), 2.86 (2H, t, J=5.7 Hz, CH₂), 3.96 (2H, q,J=7.1 Hz, CH₂), 6.27 (2H, s, CH₂), 6.66 (2H, s, H-3′ and H-5′), 6.74(1H, s, H-3), 7.57-7.69 (3H, m, H-3″, H-4″ and H-5″), 7.95 (2H, d, J=6.7Hz, H-2″ and H-6″), 8.18 (1H, s, H-6), 11.93 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 13.9 (q), 19.2 (2×q), 20.2 (q), 20.9 (t), 27.3 (t),46.2 (t), 60.6 (t), 115.0 (d), 121.5 (s), 126.7 (s), 126.1 (2×d), 128.0(2×d), 129.6 (2×d), 133.8 (d), 134.6 (d), 134.8 (s), 135.8 (s), 137.7(2×s), 140.6 (s), 140.9 (s), 141.6 (s), 145.1 (s), 155.6 (s), 157.7 (s),160.0 (s). Anal calcd for C₃₀H₃₀N₂O₅S: C, 67.90; H, 5.70; N, 5.28.Found: C, 68.05; H, 5.59; N, 5.41.

Ethyl7-(benzenesulfonyl)-8-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP070). This compound was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-7-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Brown solid; yield: 74%; m.p.: 109-110°C.; IR: 3377 (NH), 1701 (CO), 1685 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):1.19 (3H, t, J=7.0 Hz, CH₃), 2.74 (2H, t, J=6.9 Hz, CH₂), 2.93 (2H, t,J=6.9 Hz, CH₂), 4.15 (2H, q, J=7.0 Hz, CH₂), 6.49 (2H, s, CH₂), 6.92(1H, s, H-3), 7.10 (2H, d, J=8.1 Hz, H-2′ and H-6′), 7.57-7.70 (5H, m,H-3′, H-5′, H-3″, H-4″ and H-5″), 7.92 (2H, d, J=7.4 Hz, H-2″ and H-6″),8.14 (1H, s, H-6), 11.90 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.5 (q),21.3 (t), 27.6 (t), 48.9 (t), 60.5 (t), 116.6 (s), 117.9 (d), 122.9 (s),125.6 (s), 125.7 (s), 125.8 (s), 126.5 (s), 127.0 (2×d), 127.1 (2×d),127.6 (s), 128.0 (s), 128.4 (2×d), 129.5 (2×d), 131.1 (s), 133.8 (d),138.6 (d), 142.9 (d, J_(C-F)=272.4 Hz), 158.4 (s), 160.5 (s). Anal calcdfor C₂₈H₂₃F3N₂O₅S: C, 60.43; H, 4.17; N, 5.03. Found: C, 60.31; H, 4.25;N, 4.89.

Ethyl7-(benzenesulfonyl)-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP072). This compound was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-[(4-fluorophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Dark yellow solid; yield: 54%; m.p.:133-134° C.; IR: 3324 (NH), 1703 (CO), 1641 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.21 (3H, t, J=7.0 Hz, CH₃), 2.71 (2H, t, J=6.9 Hz, CH₂), 2.90(2H, t, J=6.9 Hz, CH₂), 4.17 (2H, q, J=7.0 Hz, CH₂), 6.38 (2H, s, CH₂),6.88 (1H, s, H-3), 6.96-7.05 (4H, m, H-2′, H-3′, H-5′, and H-6′),7.57-7.69 (3H, m, H-3″, H-4″ and H-5″), 7.93 (2H, d, J=7.3 Hz, H-2″ andH-6″), 8.14 (1H, s, H-6), 11.92 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):14.6 (q), 21.3 (t), 27.7 (t), 48.2 (t), 60.5 (t), 105.4 (s), 115.5 (2×d,J_(C3′-F)=21.4 Hz), 116.5 (d), 116.6 (s), 117.8 (s), 125.8 (s), 128.1(s), 128.4 (2×d), 128.6 (2×d, J_(C2′F)=8.3 Hz), 128.7 (s), 129.5 (2×d),133.9 (d), 136.0 (s), 138.5 (d), 141.2 (s), 158.4 (s), 159.9 (s), 161.8(d, J_(C4′-F)=187.6 Hz). Anal calcd for C₂₇H₂₃FN₂O₅S: C, 64.02; H, 4.58;N, 5.53. Found: C, 63.91; H, 4.44; N, 5.67.

Ethyl7-(benzenesulfonyl)-1-[3-(dimethylamino)propyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP074). This compound was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-[3-(dimethylamino)propyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Brown solid; yield: 51%; m.p.: 120-121°C.; IR: 3433 (NH), 1700 (CO), 1696 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):1.28 (3H, t, J=7.0 Hz, CH₃), 1.80-1.92 (2H, m, CH₂), 2.68-2.72 (10H, m,2×CH₃ and 2×CH₂), 2.89-2.94 (2H, m, CH₂), 4.24 (2H, q, J=7.0 Hz, CH₂),4.91-5.02 (2H, m, CH₂), 6.22 (1H, s, H-3), 7.57-7.72 (3H, m, H-3″, H-4″and H-5″), 7.87 (2H, d, J=7.6 Hz, H-2″ and H-6″), 8.21 (1H, s, H-6),11.88 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.7 (q), 21.3 (t), 28.0(t), 43.4 (2×q), 44.5 (t), 56.0 (t), 60.4 (t), 63.2 (t), 115.9 (d),123.3 (s), 125.4 (s), 126.8 (s), 127.4 (s), 127.7 (2×d), 129.4 (2×d),131.2 (s), 133.8 (d), 139.3 (d), 141.8 (s), 150.5 (s), 159.0 (s), 160.7(s). Anal calcd for C₂₅H₂₉N₃O₅S: C, 62.09; H, 6.04; N, 8.69. Found: C,61.87; H, 6.21; N, 8.84.

Propan-2-yl7-(benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP103). This compound was obtained by reaction of propan-2-yl6-[(dimethylamino)methylidene]-1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Dark yellow solid; yield: 57%; m.p.:185-186° C.; IR: 3610 (NH), 1700 (CO), 1664 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.20 (6H, d, J=6.2 Hz, 2×CH₃), 2.14 (3H, s, CH₃), 2.70 (2H, t,J=7.3 Hz, CH₂), 2.89 (2H, t, J=7.3 Hz, CH₂), 4.95-5.06 (1H, m, CH), 6.38(2H, s, CH₂), 6.59 (1H, d, J=7.0 Hz, Ar), 6.77 (1H, s, H-3), 6.85 (1H,s, H-2′), 6.92 (1H, d, J=7.2 Hz, Ar), 7.05 (1H, t, J=7.5 Hz, H-5′),7.56-7.78 (3H, m, H-3″, H-4″ and H-5″), 7.93 (2H, d, J=7.4 Hz, H-2″ andH-6″), 8.13 (1H, s, H-6), 11.90 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):21.3 (t), 21.5 (q), 22.0 (2×q), 27.7 (t), 48.8 (t), 65.4 (d), 116.4 (d),123.3 (s), 126.3 (d), 126.5 (s), 127.2 (d), 127.8 (d), 128.0 (d), 128.3(2×d), 128.7 (s), 129.1 (s), 129.2 (s), 129.4 (s), 129.5 (2×d), 130.1(s), 133.9 (d), 137.6 (d), 139.9 (s), 141.2 (s), 158.4 (s), 160.2 (s).Anal calcd for C₂₉H₂₈N₂O₅S: C, 67.42; H, 5.46; N, 5.42. Found: C, 67.60;H, 5.34; N, 5.53.

Propan-2-yl7-(benzenesulfonyl)-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP105). This compound was obtained by reaction of propan-2-yl1-(cyclopropylmethyl)-6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Yellow solid; yield: 710%; m.p.:204-205° C.; IR: 3359 (NH), 1709 (CO), 1635 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 0.23-0.28 (4H, m, 2×CH₂), 1.06-1.17 (1H, m, CH), 1.28 (6H, d,J=6.2 Hz, 2×CH₃), 2.67 (2H, t, J=7.4 Hz, CH₂), 2.90 (2H, t, J=7.4 Hz,CH₂), 5.02-5.11 (3H, m, CH₂ and CH), 6.77 (1H, s, H-3), 7.59-7.72 (3H,m, H-3″, H-4″ and H-5″), 7.96 (2H, d, J=7.6 Hz, H-2″ and H-6″), 8.15(1H, s, H-6), 11.85 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 3.5 (2×t),13.4 (d), 21.3 (t), 22.1 (2×q), 27.8 (t), 49.1 (t), 67.7 (d), 110.8 (s),116.0 (d), 125.9 (s), 127.7 (s), 128.4 (2×d), 129.5 (2×d), 130.7 (s),130.8 (s), 133.9 (d), 138.4 (d), 141.3 (s), 157.8 (s), 158.4 (s), 160.4(s). Anal calcd for C₂₅H₂₆N₂O₅S: C, 64.36; H, 5.62; N, 6.00. Found: C,64.23; H, 5.77; N, 5.93.

Propan-2-yl7-(benzenesulfonyl)-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP107). This compound was obtained by reaction of propan-2-yl6-[(dimethylamino)methylidene]-1-[(4-fluorophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Dark yellow solid; yield: 65%; m.p.:121-122° C.; IR: 3319 (NH), 1705 (CO), 1697 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.20 (6H, d, J=6.1 Hz, 2×CH₃), 2.70 (2H, t, J=7.1 Hz, CH₂), 2.90(2H, t, J=7.1 Hz, CH₂), 4.94-5.06 (1H, m, CH), 6.39 (2H, s, CH₂), 6.85(1H, s, H-3), 6.95-7.06 (4H, m, H-2′, H-3′, H-5′, and H-6′), 7.57-7.70(3H, m, H-3″, H-4″ and H-5″), 7.95 (2H, d, J=7.6 Hz, H-2″ and H-6″),8.14 (1H, s, H-6), 11.92 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 21.3 (t),22.0 (2×q), 27.7 (t), 48.2 (t), 67.9 (d), 115.5 (2×d, J_(C3′-F)=21.4Hz), 116.5 (d), 117.8 (s), 124.5 (s), 126.3 (s), 128.0 (s), 128.4 (2×d),128.5 (2×d, J_(C2′-F)=8.1 Hz), 129.5 (2×d), 130.9 (s), 133.9 (d), 136.1(s), 138.5 (d), 141.2 (s), 158.4 (s), 160.0 (s), 161.0 (s), 161.6 (d,J_(C4-F)=220.0 Hz). Anal calcd for C₂₈H₂₅FN₂O₅S: C, 64.60; H, 4.84; N,5.38. Found: C, 64.77; H, 4.69; N, 5.24.

7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP083). This compound was obtained by reaction of6-[(dimethylamino)methylidene]-1-[(3-methylphenyl)methyl]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamidewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Dark yellow solid; yield: 53%; m.p.:214-215° C.; IR: 3399 (NH), 3233 (NH), 1697 (CO), 1664 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.08 (6H, d, J=6.5 Hz, 2×CH₃), 2.13 (3H, s, CH₃),2.50-2.52 (2H, m, CH₂), 2.64-2.69 (2H, m, CH₂), 3.89-4.06 (1H, m, CH),6.34 (2H, s, CH₂), 6.64-7.07 (4H, m, H-2′, H-4′, H-5′ and H-6′),7.57-7.69 (3H, m, H-3″, H-4″ and H-5″), 7.93 (2H, d, J=6.7 Hz H-2″ andH-6″), 8.11 (1H, s, H-6), 11.80 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):21.2 (q), 22.6 (2×q), 24.6 (t), 27.0 (t), 42.9 (d), 48.9 (t), 111.0 (d),122.9 (s), 125.4 (d), 127.5 (s), 127.9 (d), 128.1 (d), 128.2 (d), 128.6(2×d), 129.0 (2×d), 131.8 (s), 133.6 (d), 134.1 (s), 137.9 (d), 138.4(s), 138.9 (s), 140.2 (s), 142.9 (s), 149.2 (s), 158.4 (s), 160.7 (s).Anal calcd for C₂₉H₂₉N₃O₄S: C, 67.55; H, 5.67; N, 8.15. Found: C, 67.77;H, 5.81; N, 8.02.

7-(Benzenesulfonyl)-N-cyclopropyl-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP084). This compound was obtained by reaction ofN-cyclopropyl-6-[(dimethylamino)methylidene]-1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamidewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Brown solid; yield: 50%; m.p.: 104-105°C.; IR: 3374 (NH), 3251 (NH), 1695 (CO), 1667 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 0.47-0.66 (4H, m, 2×CH₂), 2.13 (3H, s, CH₃), 2.51-2.58(2H, m, CH₂), 2.66-2.85 (3H, m, CH and CH₂), 6.36 (2H, s, CH₂), 6.64(1H, s, H-3), 6.68-7.08 (4H, m, H-2′, H-4′, H-5′ and H-6′), 7.61-7.79(3H, m, H-3″, H-4″ and H-5″), 7.86-7.94 (2H, m, H-2″ and H-6″), 8.07(1H, s, H-6), 8.44 (1H, d, J=4.2 Hz, NH), 11.81 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 6.2 (2×t), 21.5 (q), 21.6 (t), 23.0 (d), 27.8 (t), 48.2(t), 113.5 (s), 119.5 (s), 111.8 (d), 123.8 (d), 124.6 (s), 127.6 (d),127.7 (d), 128.0 (s), 128.2 (2×d), 128.4 (d), 129.4 (2×d), 131.2 (s),133.8 (d), 134.3 (d), 137.5 (s), 140.3 (s), 141.3 (s), 146.6 (s), 158.4(s), 162.9 (s). Anal calcd for C₂₉H₂₇N₃O₄S: C, 67.82; H, 5.30; N, 8.18.Found: 67.98; H, 5.17; N, 8.05.

7-(Benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP085). This compound was obtained by reaction of6-[(dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamidewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Dark yellow solid; yield: 61%; m.p.:152-153° C.; IR: 3417 (NH), 3359 (NH), 1663 (CO), 1641 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.08 (6H, d, J=6.5 Hz, 2×CH₃), 2.65 (2H, t, J=6.8 Hz,CH₂), 2.81 (2H, t, J=6.8 Hz, CH₂), 3.89-4.05 (1H, m, CH), 6.32 (2H, s,CH₂), 6.65 (1H, s, H-3), 6.85 (2H, d, J=8.0 Hz, H-3′ and H-5′), 6.96(2H, d, J=8.0 Hz, H-2′ and H-6′), 7.57-7.69 (3H, m, H-3″, H-4″ andH-5″), 7.93 (2H, d, J=6.8 Hz, H-2″ and H-6″), 8.05-8.08 (2H, m, H-6 andNH), 11.79 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 21.1 (q), 22.8 (2×q),23.9 (t), 26.2 (t), 42.8 (d), 48.6 (t), 111.2 (d), 122.4 (s), 127.5 (s),128.5 (2×d), 128.8 (2×d), 129.2 (2×d), 129.6 (2×d), 131.8 (s), 133.4(s), 133.9 (d), 134.3 (s), 136.5 (s), 138.2 (d), 139.6 (s), 142.9 (s),148.7 (s), 158.3 (s), 162.4 (s). Anal calcd for C₂₉H₂₉N₃O₄S: C, 67.55;H, 5.67; N, 8.15. Found: C, 67.76; H, 5.43; N, 8.01.

7-(Benzenesulfonyl)-N-cyclopropyl-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP087). This compound was obtained by reaction ofN-cyclopropyl-6-[(dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamidewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Light yellow solid; yield: 64%; m.p.:241-242° C.; IR: 3426 (NH), 3336 (NH), 1653 (CO), 1635 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 0.48-0.69 (4H, m, 2×CH₂), 2.16 (3H, s, CH₃), 2.65-2.89(4H, m, 2×CH₂), 3.33-3.45 (1H, m, CH), 6.34 (2H, s, CH₂), 6.64 (1H, s,H-3), 6.83 (2H, d, J=7.9 Hz, H-3′ and H-5′), 6.97 (2H, d, J=7.9 Hz, H-2′and H-6′), 7.60-7.69 (3H, m, H-3″, H-4″ and H-5″), 7.93 (2H, d, J=7.4Hz, H-2″ and H-6″), 8.06 (1H, s, H-6), 8.26 (1H, d, J=3.8 Hz, NH), 11.79(1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 6.22 (2×t), 21.0 (q), 21.6 (t),23.1 (d), 27.8 (t), 48.0 (t), 111.8 (d), 116.5 (s), 123.5 (s), 126.9(2×d), 128.0 (s), 128.3 (2×d), 128.8 (s), 129.2 (2×d), 129.5 (2×d),131.2 (s), 133.8 (d), 136.2 (s), 137.4 (s), 138.0 (d), 141.4 (s), 151.6(s), 158.4 (s), 162.9 (s). Anal calcd for C₂₉H₂₇N₃O₄S: C, 67.82; H,5.30; N, 8.18. Found: C, 67.69; H, 5.47; N, 7.92.

7-(Benzenesulfonyl)-1-[(4-bromophenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP096). This compound was obtained by reaction of1-[(4-bromophenyl)methyl]-6-[(dimethylamino)methylidene]-7-oxo-N-(propan-2-yl)-4,5,6,7-tetrahydro-1H-indole-2-carboxamidewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Light yellow solid; yield: 75%; m.p.:296-297° C.; IR: 3353 (NH), 3250 (NH), 1652 (CO), 1635 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.07 (6H, d, J=6.5 Hz, 2×CH₃), 2.68 (2H, t, J=7.0 Hz,CH₂), 2.87 (2H, t, J=7.0 Hz, CH₂), 3.92-4.04 (1H, m, CH), 6.34 (2H, s,CH₂), 6.71 (1H, s, H-3), 6.92 (2H, d, J=8.3 Hz, H-2′ and H-6′), 7.38(2H, d, J=8.3 Hz, H-3′ and H-5′), 7.56-7.69 (3H, m, H-3″, H-4″ andH-5″), 7.93 (2H, d, J=6.7 Hz, H-2″ and H-6″), 8.05-8.08 (2H, m, H-6 andNH), 11.80 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 21.1 (t), 22.2 (2×q),27.3 (t), 40.4 (d), 47.4 (t), 111.3 (d), 116.1 (s), 119.7 (s), 123.1(s), 127.5 (s), 127.8 (2×d), 127.9 (s), 128.8 (2×d), 129.0 (2×d), 130.8(2×d), 131.0 (s), 133.3 (d), 137.6 (d), 139.3 (s), 140.8 (s), 151.0 (s),157.9 (s), 160.2 (s). Anal calcd for C₂₈H₂₆BrN₃O₄S: C, 57.93; H, 4.51;N, 7.24. Found: C, 58.05; H, 4.77; N, 7.09.

7-(Benzenesulfonyl)-1-[(4-bromophenyl)methyl]-N-cyclopropyl-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP098). This compound was obtained by reaction of1-[(4-bromophenyl)methyl]-N-cyclopropyl-6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxamidewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Light yellow solid; yield: 73%; m.p.:281-282° C.; IR: 3342 (NH), 3096 (NH), 1641 (CO), 1633 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 0.47-0.68 (4H, m, 2×CH₂), 2.67-2.72 (3H, m, CH₂ e CH),2.83 (2H, t, J=7.0 Hz, CH₂), 6.35 (2H, s, CH₂), 6.69 (1H, s, H-3), 6.90(2H, d, J=8.2 Hz, H-2′ and H-6′), 7.38 (2H, d, J=8.2 Hz, H-3′ and H-5′),7.56-7.72 (3H, m, H-3″, H-4″ and H-5″), 7.93 (2H, d, J=7.1 Hz, H-2″ andH-6″), 8.07 (1H, s, H-6), 8.27 (1H, d, J=3.9 Hz, NH), 11.81 (1H, s, NH);¹³C nmr (DMSO-d₆) (ppm): 5.73 (2×t), 21.1 (t), 22.5 (d), 27.3 (t), 47.5(t), 111.9 (d), 120.2 (s), 121.6 (s), 127.8 (2×d), 128.2 (s), 128.7(2×d), 129.5 (s), 129.9 (2×d), 131.0 (2×d), 131.7 (s), 133.3 (d), 137.6(d), 139.8 (s), 139.9 (s), 141.3 (s), 153.2 (s), 158.4 (s), 162.6 (s).Anal calcd for C₂₈H₂₄BrN₃O₄S: C, 58.14; H, 4.18; N, 7.26. Found: C,57.95; H, 4.03; N, 7.41.

Ethyl7-(benzenesulfonyl)-3-chloro-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP076). This compound was obtained by reaction of ethyl3-chloro-6-[(dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Dark yellow solid; yield: 50%; m.p.:127-128° C.; IR: 3377 (NH), 1699 (CO), 1696 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.22 (3H, t, J=7.0 Hz, CH₃), 2.18 (3H, s, CH₃), 2.68 (2H, t,J=7.5 Hz, CH₂), 2.96 (2H, t, J=7.5 Hz, CH₂), 4.22 (2H, q, J=7.0 Hz,CH₂), 6.36 (2H, s, CH₂), 6.79 (2H, d, J=7.8 Hz, H-3′ and H-5′), 7.02(2H, d, J=7.8 Hz, H-2′ and H-6′), 7.57-7.70 (5H, m, H-3″, H-4″ andH-5″), 7.94 (2H, d, J=7.4 Hz, H-2″ and H-6″), 8.20 (1H, s, H-6), 12.06(1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.7 (q), 21.1 (q), 25.5 (t), 27.0(t), 54.3 (t), 61.5 (t), 119.2 (s), 122.4 (s), 123.6 (s), 128.6 (s),128.6 (2×d), 129.1 (2×d), 127.6 (s), 128.0 (s), 129.2 (2×d), 129.6(2×d), 133.3 (s), 133.8 (d), 136.7 (s), 139.8 (s), 143.2 (d), 143.5 (s),158.2 (s), 160.2 (s). Anal calcd for C₂₈H₂₅ClN₂O₅S: C, 62.62; H, 4.69;N, 5.22. Found: C, 62.79; H, 4.53; N, 5.09.

Ethyl7-(benzenesulfonyl)-3-iodo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP077). This compound was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-3-iodo-1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylatewith phenylsulfonyl acetonitrile after 24 h at reflux. The crude productwas purified by chromatography. Yellow solid; yield: 61%; m.p.: 121-122°C.; IR: 3302 (NH), 1703 (CO), 1641 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):1.25 (3H, t, J=7.1 Hz, CH₃), 2.17 (3H, s, CH₃), 2.60 (2H, t, J=6.7 Hz,CH₂), 2.93 (2H, t, J=6.7 Hz, CH₂), 4.21 (2H, q, J=7.1 Hz, CH₂), 6.36(2H, s, CH₂), 6.77 (2H, d, J=6.0 Hz, H-3′ and H-5′), 6.99 (2H, d, J=6.0Hz, H-2′ and H-6′), 7.60-7.76 (3H, m, H-3″, H-4″ and H-5″), 7.92-8.17(3H, m, H-6, H-2″ and H-6″), 12.01 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):13.9 (q), 20.5 (q), 22.9 (t), 26.7 (t), 49.2 (t), 60.6 (t), 75.1 (s),104.3 (s), 117.7 (s), 125.9 (2×d), 127.9 (2×d), 128.9 (2×d), 129.0(2×d), 130.5 (s), 132.5 (s), 136.0 (s), 136.1 (s), 133.5 (d), 137.2 (s),137.8 (d), 138.3 (s), 140.5 (s), 157.9 (s), 159.8 (s). Anal calcd forC₂₈H₂₅IN₂O₅S: C, 53.51; H, 4.01; N, 4.46. Found: C, 53.69; H, 3.85; N,4.61.

General Procedure for the Synthesis of Compounds of Type 10.

To a solution of the suitable tricyclic derivatives of type 9 (15 mmol)in anhydrous DMF (20 mL), NaH (0.64 g, 16 mmol) was added at 0° C., andthe reaction mixture was stirred at room temperature for 3 h. Theniodomethane (16 mmol) was added at 0° C. and the reaction mixture wasstirred at room temperature for 24 h. Then the reaction mixture waspoured onto crushed ice and the precipitate was filtered off and dried,in absence the solution was extracted with DCM (3×30 mL). The organiclayer was dried over Na₂SO₄ and the solvent was removed under reducedpressure. The crude product, containing N-methyl (10) and O-methylderivatives (11), was purified by chromatography (DCM) allowing theisolation of N-methyl derivatives and O-methyl derivatives as pureproducts.

Ethyl7-(benzenesulfonyl)-8-methoxy-1-[(4-methylphenyl)methyl]-4,5-dihydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP014). This product was obtained by reaction of PP007. Yellow solid;yield: 56%; m.p.: 114-115° C.; IR: 1704 (CO)cm⁻¹; ¹H nmr (CDCl₃) (ppm):1.26 (3H, t, J=7.1 Hz, CH₃), 2.25 (3H, s, CH₃), 2.76-2.83 (2H, m, CH₂),2.92-2.99 (2H, m, CH₂), 3.52 (3H, s, CH₃), 4.20 (2H, q, J=7.1 Hz, CH₂),6.29 (2H, s, CH₂), 6.81 (2H, d, J=7.9 Hz, H-3″ and H-5″), 6.90 (1H, s,H-3), 6.99 (2H, d, J=7.9 Hz, H-2″ and H-6″), 7.48-7.58 (3H, m, H-3′,H-4′ and H-5′), 7.95-8.00 (2H, m, H-2′ and H-6′), 8.16 (1H, s, H-6); ¹³Cnmr (CDCl₃) (ppm): 14.3 (q), 21.0 (q), 21.6 (t), 28.2 (t), 49.5 (t),54.1 (q), 60.2 (t), 115.8 (d), 119.2 (s), 124.9 (s), 125.5 (2×d), 126.1(s), 127.2 (s), 128.5 (2×d), 128.6 (2×d), 129.0 (2×d), 131.6 (s), 133.1(d), 136.1 (s), 136.4 (s), 138.1 (d), 140.8 (s), 150.6 (s), 158.2 (s),160.6 (s). Anal calcd for C₂₉H₂₈N₂O₅S: C, 67.42; H, 5.46; N, 5.42.Found: C, 67.27; H, 5.31; N, 5.65.

Ethyl8-(benzenesulfonyl)-9-methoxy-1-[(4-methylphenyl)methyl]-1,4,5,6-tetrahydropyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridine-2-carboxylate(PP055). This product was obtained by reaction of PP048. Yellow solid;yield: 50%; m.p.: 121-122° C.; IR: 1703 (CO)cm⁻¹; ¹H nmr (CDCl₃) (ppm):1.27 (3H, t, J=7.1 Hz, CH₃), 2.18-2.28 (5H, m, CH₂ and CH₃), 2.44-2.56(4H, m, 2×CH₂), 3.58 (3H, s, CH₃), 4.20 (2H, q, J=7.1 Hz, CH₂), 5.95(2H, s, CH₂), 6.69 (2H, d, J=8.0 Hz, H-3″ and H-5″), 6.92-6.96 (3H, m,H-2″, H-6″ and H-3), 7.45-7.60 (3H, m, H-3′, H-4′ and H-5′), 7.97-8.11(2H, m, H-2′ and H-6′), 8.25 (1H, s, H-7); ¹³C nmr (CDCl₃) (ppm): 14.3(q), 21.0 (q), 23.1 (t), 30.9 (t), 32.7 (t), 47.9 (t), 54.4 (q), 60.4(t), 117.6 (d), 125.3 (2×d), 125.7 (s), 127.8 (s), 128.2 (s), 128.5(2×d), 129.0 (2×d), 129.4 (2×d), 132.1 (s), 134.0 (d), 135.3 (s), 136.6(s), 138.1 (s), 141.1 (s), 142.1 (d), 145.5 (s), 153.9 (s), 160.7 (s).Anal calcd for C₃₀H₃₀N₂O₅S: C, 67.90; H, 5.70; N, 5.28. Found: C, 68.03;H, 5.58; N, 5.11.

General Procedure for the Synthesis of Compounds of Type 12 (R²=Br)

To a solution of suitable tricyclic compounds of type 9 (0.22 mmol) inanhydrous DCM (20 mL), Br₂ (0.44 mmol, 0.02 mL) was added at 0° C. andthe reaction mixture was stirred at room temperature for 24 h. Then thereaction mixture was evaporated under reduced pressure. The crude waspurified by chromatography (DCM).

Ethyl7-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP008). This product was obtained by reaction of PP007. Yellow solid;yield: 65%; m.p.: 126-127° C.; IR: 3318 (NH), 1709 (CO), 1692 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.23 (3H, t, J=6.8 Hz, CH₃), 2.17 (3H, s, CH₃),2.65 (2H, t, J=6.4 Hz, CH₂), 2.96 (2H, t, J=6.4 Hz, CH₂), 4.21 (2H, q,J=6.8 Hz, CH₂), 6.37 (2H, s, CH₂), 6.79 (2H, d, J=7.4 Hz, H-3′ andH-5′), 7.00 (2H, d, J=7.4 Hz, H-2′ and H-6′), 7.60-7.69 (3H, m, H-3″,H-4″ and H-5″), 7.94 (2H, d, J=6.7 Hz, H-2″ and H-6″), 8.19 (1H, s,H-4), 12.05 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 13.9 (q), 18.5 (q),20.5 (t), 26.5 (t), 49.0 (t), 60.6 (t), 103.8 (s), 118.0 (s), 123.4 (s),124.3 (s), 126.0 (2×d), 127.9 (2×d), 128.9 (2×d), 129.0 (2×d), 130.0(s), 133.5 (d), 135.9 (s), 136.0 (s), 138.5 (d), 140.4 (s), 149.8 (s),157.8 (s), 159.5 (s), 159.9 (s). Anal calcd for C₂₈H₂₅BrN₂O₅S: C, 57.84;H, 4.33; N, 4.82. Found: C, 58.05; H, 4.24; N, 4.99.

Ethyl8-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-9-oxo-1,4,5,6,9,10-hexahydropyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridine-2-carboxylate(PP056). This product was obtained by reaction of PP048. Light brownsolid; yield: 52%; m.p.: 124-125° C.; IR: 3377 (NH), 1708 (CO), 1701(CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.27 (3H, t, J=8.0 Hz, CH₃), 2.23 (3H,s, CH₃), 2.24-2.52 (6H, m, 3×CH₂), 4.30 (2H, q, J=8.0 Hz, CH₂), 5.79(2H, s, CH₂), 6.63 (2H, d, J=8.0 Hz, H-3″ and H-5″), 6.93 (2H, d, J=8.0Hz, H-2′ and H-6′), 7.26-7.34 (3H, m, Ar), 7.95 (2H, d, J=8.0 Hz, H-2″and H-6″) 8.32 (1H, s, H-6), 13.13 (1H, s, NH); ¹³C nmr (CDCl₃) (ppm):14.1 (q), 21.1 (q), 29.1 (t), 32.8 (t), 51.1 (t), 61.4 (t), 106.7 (s),120.6 (s), 124.7 (s), 125.8 (2×d), 127.3 (s), 127.9 (s), 128.4 (2×d),129.1 (2×d), 129.3 (2×d), 133.5 (d), 134.8 (s), 137.3 (s), 139.4 (s),142.9 (s), 145.8 (d), 159.4 (s), 159.8 (s), 160.2 (s). Anal calcd forC₂₉H₂₇BrN₂O₅S: C, 58.49; H, 4.57; N, 4.70. Found: 58.57; H, 4.69; N,4.45.

Ethyl 3-bromo1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP027). This product was obtained by reaction of PP015. Yellow solid;yield: 52%; m.p.: 122-123° C.; IR: 3399 (NH), 1700 (CO), 1641 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.23 (3H, t, J=7.0 Hz, CH₃), 2.17 (3H, s, CH₃),2.65 (2H, t, J=7.1 Hz, CH₂), 2.96 (2H, t, J=7.1 Hz, CH₂), 4.21 (2H, q,J=7.0 Hz, CH₂), 6.37 (2H, s, CH₂), 6.78 (2H, d, J=7.9 Hz, Ar), 7.00 (2H,d, J=7.9 Hz, Ar), 7.57-7.70 (3H, m, H-3″, H-4″ and H-5″), 7.94 (2H, d,J=6.9 Hz, H-2″ and H-6″), 8.19 (1H, s, H-4), 12.04 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 13.9 (q), 20.1 (q), 20.5 (t), 26.5 (t), 49.0 (t), 54.9(t), 103.7 (s), 118.0 (s), 123.6 (s), 126.0 (2×d), 127.9 (2×d), 128.9(2×d), 129.0 (2×d), 129.6 (d), 129.8 (s), 133.5 (d), 135.9 (s), 136.0(s), 138.5 (s), 140.5 (s), 157.8 (s), 159.5 (s), 163.6 (s), 164.7 (s).Anal calcd for C₂₈H₂₅BrN₂O₅S: C, 57.84; H, 4.33; N, 4.82. Found: C,57.98; H, 4.24; N, 4.68.

Ethyl 3-bromo1-(3-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP028). This product was obtained by reaction of PP016. Yellow solid;yield: 55%; m.p.: 150-151° C.; IR: 3313 (NH), 1704 (CO), 1669 (CO) cm⁻¹;¹H nmr (CDCl₃) (ppm): 1.31 (3H, t, J=7.1 Hz, CH₃), 2.27 (3H, s, CH₃),2.70-2.86 (4H, m, 2×CH₂), 4.29 (2H, q, J=7.1 Hz, CH₂), 6.08 (2H, s,CH₂), 6.77-6.86 (2H, m, Ar), 7.03 (1H, d, J=7.6 Hz, Ar), 7.13-7.22 (1H,m, Ar), 7.46-7.64 (3H, m, H-3″, H-4″ and H-5″), 7.98-8.11 (3H, m, H-2″,H-6″ and H-4), 8.82 (1H, s, NH); ¹³C nmr (CDCl₃) (ppm): 14.1 (q), 20.7(q), 21.5 (t), 27.2 (t), 50.6 (t), 61.2 (t), 104.6 (s), 118.0 (s), 120.2(s), 121.4 (s), 122.9 (d), 125.1 (s), 126.7 (d), 128.1 (2×d), 128.5 (d),128.7 (s), 128.9 (d), 129.1 (2×d), 129.4 (s), 133.6 (d), 135.7 (s),137.5 (s), 138.7 (s), 140.5 (d), 157.2 (s), 160.0 (s). Anal calcd forC₂₇H₂₃BrN₂O₅S: C, 57.15; H, 4.09; N, 4.94. Found: C, 57.01; H, 4.27; N,5.06.

Ethyl 3-bromo1-(4-chlorobenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP029). This product was obtained by reaction of PP017. Yellow solid;yield: 58%; m.p.: 106-107° C.; IR: 3342 (NH), 1701 (CO), 1694 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.22 (3H, t, J=7.1 Hz, CH₃), 2.67 (2H, t, J=7.5Hz, CH₂), 2.97 (2H, t, J=7.5 Hz, CH₂), 4.20 (2H, q, J=7.1 Hz, CH₂), 6.38(2H, s, CH₂), 6.92 (2H, d, J=8.3 Hz, H-2′ and H-6′), 7.28 (2H, d, J=8.3Hz, H-3′ and H-5′), 7.57-7.70 (3H, m, H-3″, H-4″ and H-5″), 7.94 (2H, d,J=7.0 Hz, H-2″ and H-6″), 8.19 (1H, s, H-4), 12.05 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 13.9 (q), 20.1 (t), 26.4 (t), 48.9 (t), 60.6 (t), 102.6(s), 104.0 (s), 123.3 (s), 127.9 (2×d), 128.3 (2×d), 129.0 (2×d), 129.7(2×d), 131.4 (s), 133.5 (d), 134.5 (s), 137.9 (s), 138.7 (d), 140.4 (s),141.2 (s), 142.6 (s), 157.8 (s), 159.4 (s), 164.8 (s). Anal calcd forC₂₇H₂₂BrClN₂O₅S: C, 53.88; H, 3.68; N, 4.65. Found: C, 54.02; H, 3.81;N, 4.47.

Methyl3-bromo-1-(4-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP031). This product was obtained by reaction of PP019. Yellow solid;yield: 54%; m.p.: 88-89° C.; IR: 3381 (NH), 1717 (CO), 1699 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 2.17 (3H, s, CH₃), 2.65-2.95 (4H, m, 2×CH₂),3.74 (3H, s, CH₃), 6.36 (2H, s, CH₂), 6.78 (2H, d, J=7.0 Hz, H-2′ andH-6′), 6.99 (2H, d, J=7.0 Hz, H-3′ and H-5′), 7.60-7.69 (3H, m, H-3″,H-4″ and H-5″), 7.93 (2H, d, J=6.6 Hz, H-2″ and H-6″), 8.18 (1H, s,H-4), 12.06 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 20.1 (t), 20.5 (q),26.4 (t), 49.0 (t), 51.6 (q), 103.8 (s), 118.0 (s), 123.4 (s), 124.3(s), 126.0 (2×d), 127.9 (2×d), 128.5 (s), 128.9 (2×d), 129.0 (2×d),130.0 (s), 130.7 (s), 133.5 (d), 135.9 (s), 136.0 (s), 138.5 (d), 140.4(s), 157.8 (s), 159.9 (s). Anal calcd for C₂₇H₂₃BrN₂O₅S: C, 57.15; H,4.09; N, 4.94. Found: C, 57.01; H, 4.27; N, 5.06.

Methyl3-bromo-1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP032). This product was obtained by reaction of PP020. Yellow solid;yield: 60%; m.p.: 101-102° C.; IR: 3307 (NH), 1704 (CO), 1667 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 2.32 (3H, s, CH₃), 2.71 (2H, t, J=8.1 Hz, CH₂),3.02 (2H, t, J=8.1 Hz, CH₂), 3.64 (3H, s, CH₃), 6.41 (2H, s, CH₂),6.94-7.3 (4H, m, H-3′, H-4′, H-5′ and H-6′), 7.55-7.71 (3H, m, H-3″,H-4″ and H-5″), 7.92 (2H, d, J=6.6 Hz, H-2″ and H-6″), 8.21 (1H, s,H-4), 12.04 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 18.7 (q), 20.2 (t),26.5 (t), 47.9 (t), 51.5 (q), 104.0 (s), 117.7 (s), 118.4 (s), 122.8(d), 123.2 (s), 126.1 (d), 126.3 (d), 127.8 (s), 128.0 (2×d), 129.0(2×d), 129.1 (s), 129.7 (d), 129.8 (d), 130.7 (s), 133.5 (d), 134.2 (s),137.8 (s), 140.4 (s), 157.8 (s), 159.7 (s). Anal calcd forC₂₇H₂₃BrN₂O₅S: C, 57.15; H, 4.09; N, 4.94. Found: C, 57.02; H, 3.95; N,5.08.

Ethyl3-bromo-7-[(4-chlorophenyl)sulfonyl]-1-(3-methylbenzyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP030). This product was obtained by reaction of PP018. Yellow solid;yield: 55%; m.p.: 89-90° C.; IR: 3399 (NH), 1713 (CO), 1684 (CO) cm⁻¹;¹H nmr (CDCl₃) (ppm): 1.27 (3H, t, J=7.1 Hz, CH₃), 2.36 (3H, s, CH₃),2.75-2.88 (4H, m, 2×CH₂), 4.26 (2H, q, J=7.1 Hz, CH₂), 5.95 (2H, s,CH₂), 7.01-7.24 (4H, m, Ar), 7.54 (2H, d, J=8.5 Hz, Ar), 7.94 (2H, d,J=8.5 Hz, Ar), 8.07 (1H, s, H-4), 8.90 (1H, s, NH); ¹³C nmr (CDCl₃)(ppm): 14.0 (q), 19.1 (q), 20.8 (t), 27.0 (t), 49.1 (t), 61.2 (t), 104.6(s), 120.2 (s), 120.9 (s), 125.4 (s), 126.8 (2×d), 128.3 (s), 129.3(2×d), 129.7 (s), 129.8 (2×d), 130.7 (2×d), 134.4 (s), 135.4 (s), 138.7(s), 140.3 (s), 141.1 (d), 145.4 (s), 156.9 (s), 159.8 (s). Anal calcdfor C₂₈H₂₄BrClN₂O₅S: C, 54.60; H, 3.93; N, 4.55. Found: C, 54.47; H,4.05; N, 4.39.

Ethyl7-(benzenesulfonyl)-3-bromo-1-[(2,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP033). This product was obtained by reaction of PP021. Dark yellowsolid; yield: 60%; m.p.: 301-302° C.; IR: 3273 (NH), 1709 (CO), 1664(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.12 (3H, t, J=7.1 Hz, CH₃), 2.12(3H, s, CH₃), 2.17 (3H, s, CH₃), 2.69 (2H, t, J=7.1 Hz, CH₂), 2.98 (2H,t, J=7.1 Hz, CH₂), 4.11 (2H, q, J=7.1 Hz, CH₂), 5.83 (1H, d, J=7.3 Hz,Ar), 6.11 (2H, s, CH₂), 6.72 (1H, d, J=7.3 Hz, Ar), 6.90 (1H, s, Ar),7.41-7.72 (3H, m, H-3″, H-4″ and H-5″), 7.90-8.00 (2H, m, H-2″ andH-6″), 8.19 (1H, s, H-4), 12.03 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):13.8 (q), 20.2 (t), 20.4 (q), 21.8 (q), 26.6 (t), 47.6 (t), 60.7 (t),108.3 (s), 118.3 (s), 122.3 (d), 122.8 (s), 123.2 (s), 123.5 (s), 124.5(s), 126.6 (d), 127.8 (d), 128.0 (2×d), 129.0 (2×d), 130.4 (s), 133.5(d), 135.0 (s), 138.6 (d), 140.4 (s), 148.1 (s), 149.5 (s), 157.8 (s),159.2 (s). Anal calcd for C₂₉H₂₅BrN₂O₅S: C, 58.69; H, 4.25; N, 4.72.Found: C, 58.78; H, 4.13; N, 4.59.

Ethyl7-(benzenesulfonyl)-3-bromo-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP037). This product was obtained by reaction of PP025. Dark yellowsolid; yield: 58%; m.p.: 156-157° C.; IR: 3027 (NH), 1709 (CO), 1641(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.24 (3H, t, J=7.2 Hz, CH₃), 2.06(3H, s, CH₃), 2.08 (3H, s, CH₃), 2.65 (2H, t, J=7.0 Hz, CH₂), 2.95 (2H,t, J=7.0 Hz, CH₂), 4.22 (2H, q, J=7.2 Hz, CH₂), 6.33 (2H, s, CH₂), 6.52(1H, d, J=7.7 Hz, Ar), 6.75 (1H, s, Ar), 6.93 (1H, d, J=7.7 Hz, Ar),7.57-7.73 (3H, m, H-3″, H-4″ and H-5″), 7.94 (2H, d, J=7.4 Hz, H-2″ andH-6″), 8.19 (1H, s, H-4), 12.03 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):13.9 (q), 18.9 (q), 19.4 (q), 20.1 (t), 26.5 (t), 48.9 (t), 60.6 (t),103.6 (s), 117.9 (s), 123.2 (d), 123.6 (s), 127.4 (d), 127.9 (2×d),128.6 (s), 128.8 (s), 129.0 (2×d), 129.1 (s), 129.5 (d), 129.8 (s),130.7 (s), 133.5 (d), 134.8 (s), 135.9 (s), 136.2 (s), 138.5 (d), 140.5(s), 157.8 (s), 159.5 (s). Anal calcd for C₂₉H₂₇BrN₂O₅S: C, 58.49; H,4.57; N, 4.70. Found: C, 58.56; H, 4.68; N, 4.59.

Propan-2-yl7-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP034). This product was obtained by reaction of PP022. Dark yellowsolid; yield: 55%; m.p.: 98-99° C.; IR: 3302 (NH), 1703 (CO), 1641 (CO)cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.20 (3H, s, CH₃), 1.23 (3H, s, CH₃), 2.17(3H, s, CH₃), 2.64 (2H, t, J=7.1 Hz, CH₂), 2.95 (2H, t, J=7.1 Hz, CH₂),4.97-5.13 (1H, m, CH), 6.35 (2H, s, CH₂), 6.79 (2H, d, J=7.9 Hz, H-2′and H-6′), 7.00 (2H, d, J=7.9 Hz, H-3′ and H-5′), 7.57-7.73 (3H, m,H-3″, H-4″ and H-5″), 7.94 (2H, d, J=7.1 Hz, H-2″ and H-6″), 8.18 (1H,s, H-4), 12.03 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 20.1 (t), 20.5 (q),21.5 (2×q), 26.5 (t), 48.8 (t), 68.5 (d), 103.5 (s), 117.9 (s), 124.0(s), 124.2 (s), 126.0 (2×d), 127.9 (2×d), 128.8 (s), 128.9 (2×d), 129.0(2×d), 129.1 (s), 129.6 (s), 133.5 (d), 135.9 (s), 136.0 (s), 138.5 (d),140.5 (s), 157.8 (s), 159.1 (s). Anal calcd for C₂₉H₂₇BrN₂O₅S: C, 58.49;H, 4.57; N, 4.70. Found: C, 58.59; H, 4.37; N, 4.99.

Ethyl3-bromo-7-(4-methylbenzene-1-sulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP035). This product was obtained by reaction of PP023. Dark yellowsolid; yield: 65%; m.p.: 95-96° C.; IR: 3371 (NH), 1712 (CO), 1664 (CO)cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.23 (3H, t, J=7.0 Hz, CH₃), 2.17 (3H, s,CH₃), 2.37 (3H, s, CH₃), 2.65 (2H, t, J=7.0 Hz, CH₂), 2.95 (2H, t, J=7.0Hz, CH₂), 4.21 (2H, q, J=7.0 Hz, CH₂), 6.37 (2H, s, CH₂), 6.78 (2H, d,J=7.8 Hz, H-2′ and H-6′), 7.00 (2H, d, J=7.8 Hz, H-3′ and H-5′), 7.40(2H, d, J=8.0 Hz, H-2″ and H-6″), 7.81 (2H, d, J=8.0 Hz, H-3″ and H-5″),8.17 (1H, s, H-4), 11.98 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 13.9 (q),20.1 (t), 20.5 (q), 21.0 (q), 26.5 (t), 48.9 (t), 60.6 (t), 103.8 (s),118.3 (s), 123.5 (s), 124.2 (s), 125.9 (2×d), 127.9 (s), 128.0 (2×d),128.9 (2×d), 129.5 (2×d), 132.3 (s), 135.9 (s), 136.0 (s), 137.6 (s),138.3 (d), 144.1 (s), 145.7 (s), 157.8 (s), 159.5 (s), 162.1 (s). Analcalcd for C₂₉H₂₇BrN₂O₅S: C, 58.49; H, 4.57; N, 4.70. Found: C, 58.33; H,4.65; N, 4.84.

Ethyl3-bromo-7-(metansulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP036). This product was obtained by reaction of PP024. Dark yellowsolid; yield: 57%; m.p.: 242-243° C.; IR: 3307 (NH), 1700 (CO), 1667(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.31 (3H, t, J=7.1 Hz, CH₃), 2.05(3H, s, CH₃), 2.71 (2H, t, J=7.2 Hz, CH₂), 2.99 (2H, t, J=7.2 Hz, CH₂),3.32 (3H, s, CH₃), 4.29 (2H, q, J=7.1 Hz, CH₂), 6.52 (2H, s, CH₂), 6.91(2H, d, J=7.8 Hz, H-2′ and H-6′), 7.11 (2H, d, J=7.8 Hz, H-3′ and H-5′),8.04 (1H, s, H-4), 12.36 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.1 (q),20.6 (t), 20.7 (q), 26.4 (t), 41.9 (q), 49.0 (t), 59.7 (t), 103.9 (s),118.4 (s), 123.3 (s), 124.2 (s), 126.1 (2×d), 127.8 (s), 129.0 (2×d),130.1 (s), 131.7 (s), 136.0 (s), 136.1 (s), 138.0 (d), 158.0 (s), 160.0(s), 162.3 (s). Anal calcd for C₂₃H₂₃BrN₂O₅S: C, 53.18; H, 4.46; N,5.39. Found: C, 53.05; H, 4.58; N, 5.27.

Ethyl7-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-8,9-dihydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(14, PP057). This product was obtained by reaction of PP058 (13). Darkyellow solid; yield: 54%; m.p.: 105-106° C.; IR: 3381 (NH), 1708 (CO),1664 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.25 (2H, t, J=6.8 Hz, CH₃),2.18 (3H, s, CH₃), 4.25 (2H, q, J=6.8 Hz, CH₂), 6.35 (2H, s, CH₂), 6.79(2H, d, J=7.7 Hz, H-2′ and H-6′), 7.01 (2H, d, J=7.7 Hz, H-3′ and H-5′),7.60-7.74 (5H, m, Ar), 7.94 (2H, d, J=7.3 Hz, Ar), 8.19 (1H, s, H-4),12.09 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.0 (q), 20.6 (q), 52.9(t), 60.7 (t), 103.7 (s), 106.5 (s), 111.4 (s), 119.6 (s), 123.1 (s),126.0 (2×d), 126.1 (d), 128.1 (2×d), 128.3 (d), 128.5 (d), 128.9 (2×d),129.0 (2×d), 129.5 (s), 129.6 (s), 133.5 (d), 141.1 (s), 145.1 (s),152.1 (s), 157.9 (s), 159.7 (s). Anal calcd for C₂₈H₂₃BrN₂O₅S: C, 58.04;H, 4.00; N, 4.83. Found: C, 57.94; H, 4.11; N, 4.99.

Ethyl7-(benzenesulfonyl)-3-bromo-1-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP061). This compound was obtained by reaction of PP060. Yellow solid;yield: 66%; m.p.: 135-136° C.; IR: 3324 (NH), 1709 (CO), 1685 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.21 (3H, t, J=7.1 Hz, CH₃), 2.66 (2H, t, J=7.3Hz, CH₂), 2.96 (2H, t, J=7.3 Hz, CH₂), 4.19 (2H, q, J=7.1 Hz, CH₂), 6.35(2H, s, CH₂), 6.84 (2H, d, J=8.2 Hz, H-2′ and H-6′), 7.39 (2H, d, J=8.2Hz, H-3′ and H-5′), 7.56-7.72 (3H, m, H-3″, H-4″ and H-5″), 7.94 (2H, d,J=7.6 Hz, H-2″ and H-6″), 8.18 (1H, s, H-6), 12.12 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 13.9 (q), 20.1 (t), 26.4 (t), 48.9 (t), 60.6 (t), 96.5(s), 104.0 (s), 118.1 (s), 119.9 (s), 121.6 (s), 123.2 (s), 124.3 (s),128.0 (2×d), 128.2 (2×d), 129.0 (2×d), 129.7 (s), 131.2 (2×d), 133.5(d), 138.4 (d), 140.4 (s), 149.5 (s), 157.9 (s), 159.3 (s). Anal calcdfor C₂₇H₂₂Br₂N₂O₅S: C, 50.17; H, 3.43; N, 4.33. Found: C, 50.31; H,3.18; N, 4.49.

Ethyl7-(benzenesulfonyl)-3-bromo-1-[(4-iodophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-JH-pyrrolo[3,2-h]quinoline-2-carboxylate(PP063). This compound was obtained by reaction of PP062. Light yellowsolid; yield: 67%; m.p.: 129-130° C.; IR: 3330 (NH), 1703 (CO), 1658(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.28 (3H, t, J=7.2 Hz, CH₃), 2.72(2H, t, J=7.1 Hz, CH₂), 3.03 (2H, t, J=7.1 Hz, CH₂), 4.26 (2H, q, J=7.2Hz, CH₂), 6.41 (2H, s, CH₂), 6.77 (2H, d, J=8.2 Hz, H-2′ and H-6′),7.62-7.76 (5H, m, H-3′, H-5′, H-3″, H-4″ and H-5″), 8.00 (2H, d, J=7.1Hz, H-2″ and H-6″), 8.25 (1H, s, H-6), 12.11 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 13.9 (q), 20.2 (t), 26.3 (t), 48.9 (t), 60.6 (t), 92.7(s), 104.0 (s), 112.1 (s), 118.0 (s), 123.3 (s), 124.3 (s), 127.9 (2×d),128.3 (2×d), 129.0 (2×d), 129.6 (s), 129.7 (s), 133.5 (d), 137.0 (2×d),138.8 (d), 140.4 (s), 157.9 (s), 159.3 (s), 164.7 (s). Anal calcd forC₂₇H₂₂BrIN₂O₅S: C, 46.77; H, 3.20; N, 4.04. Found: C, 46.64; H, 3.11; N,4.23.

Ethyl7-(benzenesulfonyl)-3-bromo-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP065). This compound was obtained by reaction of PP064. White solid;yield: 69%; m.p.: 192-193° C.; IR: 3553 (NH), 1703 (CO), 1637 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 0.21-0.30 (4H, m, 2×CH₂), 1.03-1.12 (1H, m, CH),1.32 (3H, t, J=6.7 Hz, CH₃), 2.58-2.65 (2H, m, CH₂), 2.91-2.95 (2H, m,CH₂), 4.30 (2H, q, J=6.7 Hz, CH₂), 5.04 (2H, d, J=6.6 Hz, CH₂),7.62-7.71 (3H, m, H-3′, H-4′ and H-5′), 7.95 (2H, d, J=7.3 Hz H-2′ andH-6′), 8.20 (1H, s, H-6), 12.00 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):3.6 (2×t), 13.8 (d), 14.5 (q), 20.7 (t), 27.0 (t), 50.1 (t), 61.1 (t),103.7 (s), 118.3 (s), 118.6 (s), 123.7 (s), 124.7 (s), 128.3 (s), 128.4(2×d), 129.5 (2×d), 129.9 (s), 134.0 (d), 138.9 (d), 141.0 (s), 158.3(s), 160.3 (s). Anal calcd for C₂₄H₂₃BrN₂O₅S: C, 54.24; H, 4.36; N,5.27. Found: C, 54.05; H, 4.18; N, 5.39.

Ethyl7-(benzenesulfonyl)-3-bromo-1-[(6-methylpyridin-3-yl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP067). This compound was obtained by reaction of PP066. White solid;yield: 67%; m.p.: 301-302° C.; IR: 3439 (NH), 1703 (CO), 1614 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.29 (3H, t, J=7.1 Hz, CH₃), 2.32 (3H, s, CH₃),3.18-3.46 (4H, m, 2×CH₂), 4.32 (2H, q, J=7.1 Hz, CH₂), 6.67 (2H, s,CH₂), 7.00-7.12 (2H, m, Ar), 7.60-7.75 (3H, m, Ar), 7.88-7.92 (1H, m,Ar), 7.98-8.06 (2H, s, Ar), 8.15-8.22 (1H, m, Ar), 9.14 (1H, s, NH); ¹³Cnmr (DMSO-d₆) (ppm): 14.4 (q), 21.3 (t), 23.9 (q), 28.7 (t), 48.1 (t),62.0 (t), 109.8 (s), 122.4 (s), 123.2 (s), 123.4 (d), 128.7 (s), 128.8(2×d), 129.0 (d), 129.5 (s), 129.6 (2×d), 131.7 (s), 132.0 (s), 134.9(d), 140.4 (s), 141.0 (s), 142.5 (d), 147.5 (d), 156.0 (s), 157.1 (s),160.4 (s). Anal calcd for C₂₇H₂₄BrN₃O₅S: C, 55.68; H, 4.15; N, 7.21.Found: C, 55.79; H, 3.97; N, 7.35.

Ethyl7-(benzenesulfonyl)-3-bromo-8-oxo-1-[(2,4,6-trimethylphenyl)methyl]-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP069). This compound was obtained by reaction of PP068. Dark yellowsolid; yield: 62%; m.p.: 110-111° C.; IR: 3342 (NH), 1660 (CO), 1642(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.28 (3H, t, J=7.1 Hz, CH₃), 1.94(6H, s, 2×CH₃), 2.19 (3H, s, CH₃), 2.68 (2H, t, J=7.4 Hz, CH₂), 3.00(2H, t, J=7.4 Hz, CH₂), 3.92 (2H, q, J=7.1 Hz, CH₂), 5.81 (2H, s, CH₂),6.77 (2H, s, H-3′ and H-5′), 7.50-8.02 (3H, m, H-2″, H-3″, H-4″, H-5″,and H-6″), 8.27 (1H, s, H-6), 12.08 (1H, s, NH); ¹³C nmr (DMSO-d₆)(ppm): 14.2 (q), 19.7 (2×q), 20.5 (t), 20.8 (q), 27.2 (t), 46.9 (t),61.1 (t), 101.0 (s), 115.7 (s), 126.6 (2×d), 127.0 (s), 128.4 (2×d),129.5 (2×d), 132.0 (s), 134.0 (d), 135.1 (d), 136.2 (s), 137.0 (2×s),137.4 (s), 138.2 (s), 141.1 (s), 142.1 (s), 156.1 (s), 158.3 (s), 160.3(s). Anal calcd for C₃₀H₂₉BrN₂O₅S: C, 59.11; H, 4.80; N, 4.60. Found: C,58.94; H, 4.69; N, 4.75.

Ethyl7-(benzenesulfonyl)-3-bromo-8-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP071). This compound was obtained by reaction of PP070. Dark yellowsolid; yield: 75%; m.p.: 185-186° C.; IR: 3439 (NH), 1703 (CO), 1658(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.18 (3H, t, J=7.0 Hz, CH₃), 2.69(2H, t, J=7.4 Hz, CH₂), 2.99 (2H, t, J=7.4 Hz, CH₂), 4.18 (2H, q, J=7.0Hz, CH₂), 6.49 (2H, s, CH₂), 7.11 (2H, d, J=7.9 Hz, H-2′ and H-6′),7.59-7.71 (5H, m, H-3′, H-5′, H-3″, H-4″ and H-5″), 7.93 (2H, d, J=7.3Hz, H-2″ and H-6″), 8.19 (1H, s, H-6), 12.01 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 14.3 (q), 20.6 (t), 26.9 (t), 49.8 (t), 61.1 (t), 104.6(s), 118.7 (s), 123.7 (s), 124.9 (s), 125.7 (s), 125.8 (s), 127.0 (2×d),127.1 (2×d), 127.7 (s), 128.1 (s), 128.4 (2×d), 128.5 (s), 129.5 (2×d),130.2 (s), 134.0 (d), 139.0 (d), 142.6 (d, J_(C-F)=251.8 Hz), 158.3 (s),159.8 (s). Anal calcd for C₂₈H₂₂BrF₃N₂O₅S: C, 52.92; H, 3.49; N, 4.41.Found: C, 53.07; H, 3.61; N, 4.28.

Ethyl7-(benzenesulfonyl)-3-bromo-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP073). This compound was obtained by reaction of PP072. Yellow solid;yield: 64%; m.p.: 136-137° C.; IR: 3313 (NH), 1703 (CO), 1641 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.21 (3H, t, J=7.1 Hz, CH₃), 2.66 (2H, t, J=7.6Hz, CH₂), 2.96 (2H, t, J=7.6 Hz, CH₂), 4.21 (2H, q, J=7.1 Hz, CH₂), 6.38(2H, s, CH₂), 6.93-7.07 (4H, m, H-2′, H-3′, H-5′, and H-6′), 7.58-7.71(3H, m, H-3″, H-4″ and H-5″), 7.94 (2H, d, J=7.4 Hz, H-2″ and H-6″),8.19 (1H, s, H-6), 12.03 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.4 (q),20.6 (t), 26.9 (t), 49.1 (t), 61.1 (t), 104.4 (s), 115.6 (2×d,J_(C3′-F)=21.4 Hz), 118.6 (s), 123.9 (s), 124.8 (s), 128.4 (2×d), 128.5(s), 128.6 (2×d, J_(C2′-F)=8.3 Hz), 128.7 (s), 129.5 (2×d), 130.2 (s),134.0 (d), 135.5 (s), 139.0 (d), 141.0 (s), 150.1 (s), 158.4 (s), 161.5(d, J_(C4′-F)=243.7 Hz). Anal calcd for C₂₇H₂₂BrFN₂O₅S: C, 55.39; H,3.79; N, 4.79. Found: C, 55.22; H, 3.87; N, 4.65.

Ethyl7-(benzenesulfonyl)-1-[3-(dimethylamino)propyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP075). This compound was obtained by reaction of PP074. Dark yellowsolid; yield: 56%; m.p.: 255-256° C.; IR: 3410 (NH), 1664 (CO), 1606(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.26 (3H, t, J=7.0 Hz, CH₃),1.82-1.96 (2H, m, CH₂), 2.67-2.72 (10H, m, 2×CH₃ and 2×CH₂), 2.93-2.98(2H, m, CH₂), 4.24 (2H, q, J=7.0 Hz, CH₂), 4.90-5.02 (2H, m, CH₂),7.57-7.72 (3H, m, H-3″, H-4″ and H-5″), 7.88 (2H, d, J=7.6 Hz, H-2″ andH-6″), 8.23 (1H, s, H-6), 11.91 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):14.6 (q), 21.5 (t), 27.8 (t), 43.4 (2×q), 44.7 (t), 56.5 (t), 60.1 (t),63.6 (t), 105.9 (s), 123.0 (s), 124.7 (s), 126.4 (s), 127.0 (s), 127.5(2×d), 129.4 (2×d), 132.6 (s), 133.5 (d), 139.7 (d), 141.5 (s), 151.5(s), 158.7 (s), 160.9 (s). Anal calcd for C₂₅H₂₉N₃O₅S: C, 62.09; H,6.04; N, 8.69. Found: C, 61.87; H, 6.21; N, 8.84.

Propan-2-yl7-(benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP104). This compound was obtained by reaction of PP103. Light brownsolid; yield: 68%; m.p.: 187-188° C.; IR: 3302 (NH), 1683 (CO), 1680(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.20 (6H, d, J=6.2 Hz, 2×CH₃), 2.15(3H, s, CH₃), 2.64 (2H, t, J=7.4 Hz, CH₂), 2.95 (2H, t, J=7.4 Hz, CH₂),4.99-5.07 (1H, m, CH), 6.36 (2H, s, CH₂), 6.60 (1H, d, J=7.5 Hz, Ar),6.79 (1H, s, H-2′), 6.95 (1H, d, J=7.3 Hz, Ar), 7.07 (1H, t, J=7.5 Hz,H-5′), 7.57-7.71 (3H, m, H-3″, H-4″ and H-5″), 7.94 (2H, d, J=7.3 Hz,H-2″ and H-6″), 8.19 (1H, s, H-6), 12.03 (1H, s, NH); ¹³C nmr (DMSO-d₆)(ppm): 20.6 (t), 21.5 (q), 21.9 (2×q), 27.0 (t), 49.6 (t), 68.9 (d),103.9 (s), 118.5 (s), 123.5 (s), 124.5 (s), 127.1 (s), 127.4 (d), 128.1(d), 128.4 (2×d), 128.8 (d), 129.5 (2×d), 130.0 (d), 130.1 (s), 134.0(d), 137.8 (d), 138.9 (s), 139.0 (s), 139.3 (s), 141.0 (s), 158.4 (s),159.6 (s). Anal calcd for C₂₉H₂₇BrN₂O₅S: C, 58.49; H, 4.57; N, 4.70.Found: C, 58.61; H, 4.39; N, 4.88.

Propan-2-yl7-(benzenesulfonyl)-3-bromo-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP106). This compound was obtained by reaction of PP105. Yellow solid;yield: 72%; m.p.: 196-197° C.; IR: 3319 (NH), 1701 (CO), 1685 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 0.22-0.31 (4H, m, 2×CH₂), 1.10-1.34 (7H, m,2×CH₃ e CH), 2.63 (2H, t, J=7.4 Hz, CH₂), 2.95 (2H, t, J=7.4 Hz, CH₂),5.06-5.14 (3H, m, CH₂ and CH), 7.63-7.71 (3H, m, H-3″, H-4″ and H-5″),7.97-8.07 (2H, m, H-2″ and H-6″), 8.21 (1H, s, H-6), 11.99 (1H, s, NH);¹³C nmr (DMSO-d₆) (ppm): 3.6 (2×t), 13.8 (d), 20.7 (t), 22.1 (2×q), 27.1(t), 50.0 (t), 69.0 (d), 103.5 (s), 118.4 (s), 124.1 (s), 124.7 (s),128.2 (s), 128.5 (2×d), 129.5 (2×d), 129.8 (s), 134.0 (d), 138.9 (d),141.1 (s), 150.4 (s), 158.3 (s), 159.9 (s). Anal calcd forC₂₅H₂₅BrN₂O₅S: C, 55.05; H, 4.62; N, 5.14. Found: C, 55.16; H, 4.43; N,5.02.

Propan-2-yl7-(benzenesulfonyl)-3-bromo-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP108). This compound was obtained by reaction of PP107. Yellow solid;yield: 85%; m.p.: 135-136° C.; IR: 3307 (NH), 1703 (CO), 1646 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.20 (6H, d, J=6.1 Hz, 2×CH₃), 2.65 (2H, t,J=7.4 Hz, CH₂), 2.96 (2H, t, J=7.4 Hz, CH₂), 4.97-5.09 (1H, m, CH), 6.38(2H, s, CH₂), 6.94-7.08 (4H, m, H-2′, H-3′, H-5′ and H-6′), 7.58-7.71(3H, m, H-3″, H-4″ and H-5″), 7.95 (2H, d, J=7.5 Hz, H-2″ and H-6″),8.19 (1H, s, H-6), 12.03 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 20.6 (t),21.9 (2×q), 26.9 (t), 49.0 (t), 69.0 (d), 104.1 (s), 115.6 (2×d,J_(C3′-F)=21.4 Hz), 118.5 (s), 124.2 (s), 124.7 (s), 128.4 (2×d), 128.6(2×d, J_(C2′-F)=8.1 Hz), 129.5 (2×d), 129.9 (s), 134.0 (d), 135.5 (s),138.9 (d), 141.0 (s), 150.1 (s), 158.4 (s), 159.5 (s), 161.6 (d,J_(C4′-F)=242.9 Hz). Anal calcd for C₂₈H₂₄BrFN₂O₅S: C, 56.10; H, 4.04;N, 4.67. Found: C, 55.98; H, 3.89; N, 4.74.

7-(Benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP091). This compound was obtained by reaction of PP083. White solid;yield: 57%; m.p.: 206-207° C.; IR: 3419 (NH), 3406 (NH), 1629 (CO), 1622(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.15 (6H, s, 2×CH₃), 1.24 (3H, s,CH₃), 2.59-2.67 (2H, m, CH₂), 2.91-2.98 (2H, m, CH₂), 3.96-4.17 (1H, m,CH), 6.13 (2H, s, CH₂), 6.86-7.23 (4H, m, H-2′, H-4′, H-5′ and H-6′),7.62-7.89 (3H, m, H-3″, H-4″ and H-5″), 7.88-7.94 (2H, m, H-2″ andH-6″), 8.24 (1H, s, H-6), 12.01 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):20.1 (t), 20.9 (q), 21.8 (2×q), 40.9 (d), 96.8 (s), 116.6 (s), 122.7(s), 124.3 (d), 126.0 (s), 127.0 (s), 127.8 (2×d), 127.9 (d), 128.0 (s),128.1 (d), 128.9 (2×d), 131.5 (s), 133.3 (d), 133.4 (d), 137.2 (s),137.8 (d), 138.3 (s), 140.7 (s), 158.0 (s), 158.9 (s). Anal calcd forC₂₉H₂₈BrN₃O₄S: C, 58.59; H, 4.75; N, 7.07. Found: C, 58.44; H, 4.63; N,7.22.

7-(Benzenesulfonyl)-N-cyclopropyl-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP092). This compound was obtained by reaction of PP084. Light brownsolid; yield: 50%; m.p.: 142-143° C.; IR: 3474 (NH), 3331 (NH), 1697(CO), 1645 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 0.38-0.61 (4H, m, 2×CH₂),2.30 (3H, s, CH₃), 2.55 (2H, t, J=6.9 Hz, CH₂), 2.93 (2H, t, J=6.9 Hz,CH₂), 3.33-3.40 (1H, m, CH), 6.20 (2H, s, CH₂), 6.99-7.21 (4H, m, H-2′,H-4′, H-5′ and H-6′), 7.55-7.71 (5H, m, H-3″, H-4″ and H-5″), 7.94 (2H,d, J=7.2 Hz, H-2″ and H-6″), 8.28 (1H, s, H-6), 9.12 (1H, s, NH), 11.96(1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 6.7 (2×t), 21.3 (q), 22.8 (t),23.8 (d), 27.2 (t), 48.9 (t), 102.3 (s), 122.5 (s), 124.8 (d), 125.0(s), 127.8 (d), 128.1 (d), 128.4 (d), 128.8 (2×d), 129.4 (2×d), 132.9(s), 133.6 (d), 134.1 (s), 137.3 (s), 138.5 (d), 139.4 (s), 141.3 (s),143.4 (s), 146, 1 (s), 158.3 (s), 163.4 (s). Anal calcd forC₂₉H₂₆BrN₃O₄S: C, 58.79; H, 4.42; N, 7.09. Found: 58.91; H, 4.29; N,7.22.

7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP086). This compound was obtained by reaction of PP085. Dark greensolid; yield: 59%; m.p.: 102-103° C.; IR: 3422 (NH), 3324 (NH), 1661(CO), 1652 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.07 (6H, d, J=6.5 Hz,2×CH₃), 2.18 (3H, s, CH₃), 2.62-2.69 (2H, m, CH₂), 2.85-2.90 (2H, m,CH₂), 3.91-4.08 (1H, m, CH), 6.02 (2H, s, CH₂), 6.90-7.10 (4H, m, H-2′,H-3′, H-5′ and H-6′), 7.61-7.77 (3H, m, H-3″, H-4″ and H-5″), 7.92-8.10(4H, m, H-2″, H-6″, H-6 and NH), 11.91 (1H, s, NH); ¹³C nmr (DMSO-d₆)(ppm): 20.1 (t), 22.8 (2×q), 24.6 (t), 42.9 (d), 48.9 (t), 101.8 (s),122.7 (s), 124.5 (s), 128.8 (2×d), 129.0 (2×d), 129.3 (2×d), 129.7(2×d), 133.2 (s), 133.6 (d), 133.8 (s), 137.0 (s), 138.7 (d), 140.1 (s),141.3 (s), 143.5 (s), 145.8 (s), 158.4 (s), 161.2 (s). Anal calcd forC₂₉H₂₈BrN₃O₄S: C, 58.59; H, 4.75; N, 7.07. Found: C, 58.43; H, 4.88; N,7.33.

7-(Benzenesulfonyl)-3-bromo-N-cyclopropyl-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP088). This compound was obtained by reaction of PP087. Orange solid;yield: 69%; m.p.: 102-103° C.; IR: 3461 (NH), 3387 (NH), 1665 (CO), 1653(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 0.99-1.27 (4H, m, 2×CH₂), 2.17 (3H,s, CH₃), 2.64-2.94 (4H, m, 2×CH₂), 3.28-3.45 (1H, m, CH), 6.18 (2H, s,CH₂), 6.86-7.08 (4H, m, H-2′, H-3′, H-5′ and H-6′), 7.54-7.72 (3H, m,H-3″, H-4″ and H-5″), 7.78-8.06 (2H, m, H-2″ and H-6″), 8.08 (1H, s,H-6), 9.08 (1H, s, NH), 12.52 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 8.22(2×t), 21.2 (q), 23.6 (t), 24.9 (d), 27.1 (t), 48.3 (t), 102.4 (s),122.5 (s), 124.6 (s), 128.4 (2×d), 129.1 (2×d), 129.2 (2×d), 129.6(2×d), 132.9 (s), 133.7 (d), 133.9 (s), 136.5 (s), 138.4 (d), 139.6 (s),141.2 (s), 142.9 (s), 146.4 (s), 158.4 (s), 166.2 (s). Anal calcd forC₂₉H₂₆BrN₃O₄S: C, 58.79; H, 4.42; N, 7.09. Found: C, 58.65; H, 4.33; N,7.25.

7-(Benzenesulfonyl)-3-bromo-1-[(4-bromophenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP097). This compound was obtained by reaction of PP096. White solid;yield: 67%; m.p.: 161-162° C.; IR: 3416 (NH), 3348 (NH), 1669 (CO), 1658(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.04 (6H, d, J=6.4 Hz, 2×CH₃), 2.61(2H, t, J=7.3 Hz, CH₂), 2.89 (2H, t, J=7.3 Hz, CH₂), 3.91-4.01 (1H, m,CH), 6.03 (2H, s, CH₂), 7.03 (2H, d, J=8.1 Hz, H-2′ and H-6′), 7.39 (2H,d, J=8.1 Hz, H-3′ and H-5′), 7.57-7.70 (3H, m, H-3″, H-4″ and H-5″),7.94 (2H, d, J=7.1 Hz, H-2″ and H-6″), 8.11 (1H, s, H-6), 8.26 (2H, d,J=7.9 Hz, NH), 11.97 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 20.1 (t),21.8 (2×q), 26.6 (t), 40.9 (d), 47.9 (t), 97.0 (s), 114.1 (s), 116.6(s), 120.2 (s), 121.4 (s), 122.7 (s), 125.9 (s), 127.0 (s), 127.9 (2×d),129.0 (2×d), 129.4 (2×d), 131.1 (2×d), 131.4 (s), 133.4 (d), 137.9 (d),140.7 (s), 158.1 (s), 158.7 (s). Anal calcd for C₂₈H₂₅Br₂N₃O₄S: C,51.00; H, 3.82; N, 6.37. Found: C, 51.15; H, 3.74; N, 6.45.

7-(Benzenesulfonyl)-3-bromo-1-[(4-bromophenyl)methyl]-N-cyclopropyl-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamidePP099). This compound was obtained by reaction of PP098. Yellow solid;yield: 70%; m.p.: 165-166° C.; IR: 3381 (NH), 3319 (NH), 1669 (CO), 1633(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.05-12 (4H, m, 2×CH₂), 2.53-2.56(2H, m, CH₂), 3.36-3.43 (2H, m, CH₂), 4.28-4.48 (1H, m, CH), 6.38 (2H,s, CH₂), 7.05 (2H, d, J=7.9 Hz, H-2′ and H-6′), 7.36 (2H, d, J=7.9 Hz,H-3′ and H-5′), 7.50-7.72 (3H, m, H-3″, H-4″ and H-5″), 8.01 (2H, d,J=7.1 Hz, H-2″ and H-6″), 9.11 (2H, s, H-6 and NH), 12.42 (1H, s, NH);¹³C nmr (DMSO-d₆) (ppm): 5.70 (2×t), 22.3 (d), 23.1 (t), 26.3 (t), 93.2(s), 117.4 (s), 120.1 (s), 121.1 (s), 121.3 (s), 123.2 (s), 128.2 (2×d),129.0 (2×d), 129.1 (2×d), 129.4 (s), 131.1 (2×d), 133.7 (d), 138.0 (d),141.1 (s), 141.8 (s), 156.2 (s), 159.7 (s), 160.0 (s). Anal calcd forC₂₈H₂₃Br₂N₃O₄S: C, 51.16; H, 3.53; N, 6.39. Found: 51.02; H, 3.39; N,6.51.

General Procedure for the Synthesis of Compounds of Type 9 (R¹=COOH) and12 (R¹=COOH)

To a solution of the suitable derivatives of type 9,12 (R¹=COOEt) (0.5mmol) in EtOH (10 mL), KOH (0.42 g, 7.5 mmol) was added and the reactionmixture was heated at reflux for 24 h. After cooling, the solvent wasremoved under reduced pressure. The residue was added of water and thesolution was acidified with HCl 6M. The solid formed was filtered off,dried and recrystallized from ethanol.

7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP090). This compound was obtained by reaction of PP016. Yellowsolid; yield: 80%; m.p.: 189-190° C.; IR: 3384 (NH), 3323 (NH), 1702(CO), 1667 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 2.20 (3H, s, CH₃),2.71-2.94 (4H, m, 2×CH₂), 6.46 (2H, s, CH₂), 6.66 (1H, d, J=7.2 Hz, Ar),6.82-7.15 (4H, m, H-3 and Ar), 7.62-7.75 (3H, m, H-3″, H-4″ and H-5″),7.98 (2H, d, J=6.8 Hz, H-2″ and H-6″), 8.17 (1H, s, H-6), 11.98 (1H, s,NH), 12.69 (1H, s, OH); ¹³C nmr (DMSO-d₆) (ppm): 21.4 (t), 21.5 (q),27.8 (t), 48.6 (t), 101.5 (s), 116.0 (s), 116.3 (d), 123.1 (s), 123.4(d), 127.1 (s), 127.2 (d), 127.8 (d), 128.3 (d), 128.7 (2×d), 129.5(2×d), 130.1 (d), 133.9 (d), 137.6 (s), 137.7 (s), 140.1 (s), 141.2 (s),141.8 (s), 158.4 (s), 158.8 (s), 162.3 (s). Anal calcd for C₂₆H₂₂N₂O₅S:C, 65.81; H, 4.67; N, 5.90. Found: C, 65.66; H, 4.84; N, 6.12.

7-(Benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP081). This compound was obtained by reaction of PP028. Yellowsolid; yield: 87%; m.p.: 177-178° C.; IR: 3502 (NH), 3302 (OH), 1675(CO), 1641 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 2.15 (3H, s, CH₃), 2.65(2H, t, J=7.5 Hz, CH₂), 2.95 (2H, t, J=7.5 Hz, CH₂), 6.42 (2H, s, CH₂),6.60 (1H, d, J=7.5 Hz, Ar), 6.79 (1H, s, H-2′), 6.95 (1H, d, J=7.5 Hz,Ar), 7.07 (1H, t, J=7.5 Hz, H-5′), 7.56-7.73 (3H, m, H-3″, H-4″ andH-5″), 7.94 (2H, d, J=7.6 Hz, H-2″ and H-6″), 8.17 (1H, s, H-6), 12.05(1H, s, NH), 13.23 (1H, s, OH); ¹³C nmr (DMSO-d₆) (ppm): 20.2 (t), 21.0(q), 26.5 (t), 48.9 (t), 103.4 (s), 117.8 (s), 122.9 (d), 124.7 (s),124.8 (s), 126.9 (d), 127.5 (d), 127.9 (2×d), 128.3 (d), 129.0 (2×d),129.5 (s), 133.5 (d), 137.3 (s), 138.4 (d), 139.1 (s), 140.5 (s), 146.4(s), 149.8 (s), 157.9 (s), 161.1 (s). Anal calcd for C₂₆H₂₁BrN₂O₅S: C,56.43; H, 3.82; N, 5.06. Found: C, 56.56; H, 3.99; N, 4.87.

7-(Benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP078). This compound was obtained by reaction of PP007. Yellowsolid; yield: 75%; m.p.: 246-147° C.; IR: 3421 (NH), 3342 (OH), 1709(CO), 1646 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 2.17 (3H, s, CH₃),2.69-2.72 (2H, m, CH₂), 2.85-2.88 (2H, m, CH₂), 6.39 (2H, s, CH₂),6.67-6.83 (3H, m, H-3, H-3′ and H-5′), 6.98 (2H, d, J=7.9 Hz, H-2′ andH-6′), 7.56-7.73 (3H, m, H-3″, H-4″ and H-5″), 7.93 (2H, d, J=7.5 Hz,H-2″ and H-6″), 8.11 (1H, s, H-6), 11.89 (1H, s, OH), 12.01 (1H, s, NH);¹³C nmr (DMSO-d₆) (ppm): 20.5 (q), 20.9 (t), 27.2 (t), 47.8 (t), 115.8(d), 122.5 (s), 126.0 (2×d), 127.8 (2×d), 128.8 (2×d), 129.0 (2×d),131.8 (s), 132.1 (s), 133.4 (d), 133.8 (s), 134.2 (s), 136.9 (s), 137.9(d), 140.2 (s), 143.4 (s), 148.0 (s), 158.7 (s), 162.6 (s). Anal calcdfor C₂₆H₂₂N₂O₅S: C, 65.81; H, 4.67; N, 5.90. Found: C, 65.97; H, 4.75;N, 5.71.

7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP079). This compound was obtained by reaction of PP008. Yellowsolid; yield: 75%; m.p.: 164-165° C.; IR: 3450 (NH), 3336 (OH), 1662(CO), 1657 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 2.14 (3H, s, CH₃),2.51-2.63 (2H, m, CH₂), 2.73-2.76 (2H, m, CH₂), 6.46 (2H, s, CH₂),6.85-6.99 (4H, m, H-2′, H-3′, H-5′ and H-6′), 7.50-7.63 (3H, m, H-3″,H-4″ and H-5″), 7.93-7.96 (3H, m, H-6, H-2″ and H-6″), 11.87 (1H, s,OH), 12.09 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 20.6 (q), 20.7 (t),26.9 (t), 48.1 (t), 103.6 (s), 122.6 (s), 126.6 (2×d), 127.6 (2×d),128.5 (2×d), 128.6 (2×d), 132.8 (d), 133.3 (s), 133.8 (s), 134.1 (s),137.3 (d), 138.9 (s), 140.1 (s), 141.3 (s), 143.7 (s), 146.1 (s), 158.5(s), 160.5 (s). Anal calcd per C₂₆H₂₁BrN₂O₅S: C, 56.43; H, 3.82; N,5.06. Found: C, 56.29; H, 3.71; N, 5.14.

7-(Benzenesulfonyl)-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP094). This compound was obtained by reaction of PP025. Yellowsolid; yield: 72%; m.p.: 260-261° C.; IR: 3318 (NH), 3193 (OH), 1709(CO), 1645 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 2.03 (3H, s, CH₃), 2.06(3H, s, CH₃), 2.68 (2H, t, J=6.5 Hz, CH₂), 2.87 (2H, t, J=6.5 Hz, CH₂),6.36 (2H, s, CH₂), 6.54 (1H, d, J=7.6 Hz, H-6′), 6.74 (1H, s, H-3), 6.83(1H, s, H-2′), 6.90 (1H, d, J=7.6 Hz, H-5′), 7.56-7.68 (3H, m, H-3″,H-4″ and H-5″), 7.93 (2H, d, J=7.3 Hz, H-2″ and H-6″), 8.12 (1H, s,H-6), 11.94 (1H, s, NH), 12.51 (1H, s, OH); ¹³C nmr (DMSO-d₆) (ppm):18.9 (q), 19.5 (q), 20.9 (t), 27.3 (t), 47.8 (t), 115.8 (d), 117.0 (s),123.2 (d), 123.6 (s), 126.5 (s), 127.3 (d), 127.4 (s), 127.8 (2×d),129.0 (2×d), 129.3 (d), 130.4 (s), 133.4 (d), 134.4 (s), 135.7 (s),137.0 (s), 138.0 (d), 140.7 (s), 150.5 (s), 157.8 (s), 161.8 (s). Analcalcd for C₂₇H₂₄N₂O₅S: C, 66.38; H, 4.95; N, 5.73. Found: C, 66.22; H,5.07; N, 5.88.

7-(Benzenesulfonyl)-3-bromo-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP095). This compound was obtained by reaction of PP037. Darkyellow solid; yield: 77%; m.p.: 249-150° C.; IR: 3485 (NH), 3365 (OH),11653 (CO), 1648 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.99 (3H, s, CH₃),2.03 (3H, s, CH₃), 2.42-2.51 (2H, m, CH₂), 2.68-71 (2H, m, CH₂), 6.32(2H, s, CH₂), 6.63 (1H, d, J=7.6 Hz, H-6′), 6.79-6.84 (2H, m, H-2′ andH-5′), 7.51-7.63 (3H, m, H-3″, H-4″ and H-5″), 7.81 (1H, s, H-6), 7.92(2H, d, J=7.3 Hz, H-2″ and H-6″), 11.91 (1H, s, NH), 12.54 (1H, s, OH);¹³C nmr (DMSO-d₆) (ppm): 19.3 (q), 19.9 (q), 21.3 (t), 27.5 (t), 48.4(t), 97.6 (s), 110.8 (s), 115.2 (s), 124.5 (d), 125.9 (s), 127.6 (s),127.9 (2×d), 128.5 (d), 129.1 (2×d), 129.5 (d), 133.2 (d), 134.5 (s),135.6 (s), 135.8 (s), 137.6 (d), 138.3 (s), 142.2 (s), 152.0 (s), 163.4(s), 163.8 (s). Anal calcd for C₂₇H₂₃BrN₂O₅S: C, 57.15; H, 4.09; N,4.94. Found: C, 57.00; H, 4.26; N, 5.09.

General Procedure for the Synthesis of Compounds of Type 9 (R¹=CONHR⁴)and 12 (R¹=CONHR⁴)

To a suspension of the suitable acid derivatives 9,12 (R¹=COOH) (0.19mmol) in anhydrous DMF (3 mL) N,N-diisopropylethylamine (0.19 mL, 1.09mmol), 1-hydroxybenzotriazole hydrate (0.04 g, 0.30 mmol), and EDC (0.05g, 0.28 mmol) were added. The reaction mixture was stirred at roomtemperature for 10 min. Then the proper amine (0.76 mmol) was added inone portion, and the resulting suspension was stirred at roomtemperature for 16 h. Then the reaction mixture was poured onto crushedice and the solid formed was filtered off, dried and recrystallized fromethanol.

7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP093). This compound was obtained by reaction of PP090 with ammoniumcarbonate. Yellow solid; yield: 54%; m.p.: 269-270° C.; IR: 3421 (NH),3342-3313 (NH₂), 1657 (CO), 1637 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 2.13(3H, s, CH₃), 2.66 (2H, t, J=6.5 Hz, CH₂), 2.85 (2H, t, J=6.5 Hz, CH₂),6.42 (2H, s, CH₂), 6.64 (1H, d, J=7.4 Hz, Ar), 6.77 (2H, s, H-3 andH-2′), 6.90 (1H, d, J=7.4 Hz, Ar), 7.03 (1H, t, J=7.4 Hz, H-5′),7.56-7.74 (5H, m, H-3″, H-4″, H-5″ and NH₂), 7.92 (2H, d, J=6.9 Hz, H-2″and H-6″), 8.07 (1H, s, H-6), 11.79 (1H, s, NH); ¹³C nmr (DMSO-d₆)(ppm): 21.5 (q), 21.6 (t), 27.9 (t), 48.3 (t), 110.0 (s), 116.7 (s),112.4 (d), 123.7 (d), 127.5 (d), 127.7 (d), 128.0 (s), 128.3 (2×d),128.5 (d), 129.2 (s), 129.4 (2×d), 130.7 (s), 132.0 (d), 133.8 (d),137.5 (s), 140.5 (s), 141.4 (s), 151.5 (s), 158.4 (s), 163.4 (s). Analcalcd for C₂₆H₂₃N₃O₄S: C, 65.94; H, 4.90; N, 8.87. Found: C, 65.81; H,5.04; N, 9.03.

7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP082). This compound was obtained by reaction of PP081 with ammoniumcarbonate. White solid; yield: 51%; m.p.: 253-254° C.; IR: 3502 (NH),3387-3365 (NH₂), 1658 (CO), 1649 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 2.15(3H, s, CH₃), 2.56-2.64 (2H, m, CH₂), 2.86-2.93 (2H, m, CH₂), 6.11 (2H,s, CH₂), 6.74-7.11 (4H, m, H-2′, H-4′, H-5′ and H-6′), 7.56-7.78 (7H, m,H-3″, H-4″, H-5″ and NH₂), 7.94 (2H, d, J=6.8 Hz, H-2″ and H-6″), 8.06(1H, s, H-6), 11.93 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 21.3 (q), 24.1(t), 26.7 (t), 48.6 (t), 108.8 (s), 122.7 (s), 125.2 (d), 127.9 (d),128.0 (d), 128.8 (2×d), 128.4 (d), 128.6 (s), 129.4 (2×d), 133.6 (d),134.2 (s), 137.5 (d), 137.9 (s), 138.8 (s), 140.0 (s), 141.1 (s), 143.5(s), 146.7 (s), 158.4 (s), 163.0 (s). Anal calcd per C₂₆H₂₂BrN₃O₄S: C,56.53; H, 4.01; N, 7.61. Trovato: C, 56.41; H, 4.14; N, 7.50.

7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP080). This compound was obtained by reaction of PP078 with ammoniumcarbonate. Dark yellow solid; yield: 50%; m.p.: 138-139° C.; IR: 3393(NH), 3345-3307 (NH₂), 1667 (CO), 1655 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 2.16 (3H, s, CH₃), 2.67-2.72 (2H, m, CH₂), 2.82-3.06 (2H, m,CH₂), 6.40 (2H, s, CH₂), 6.77-6.83 (3H, m, H-3, H-3′ and H-5′), 6.96(2H, d, J=7.9 Hz, H-2′ and H-6′), 7.20 (2H, s, NH₂), 7.56-7.73 (3H, m,H-3″, H-4″ and H-5″), 7.92 (2H, d, J=7.0 Hz, H-2″ and H-6″), 8.06 (1H,s, H-6), 11.81 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 21.0 (t), 21.6 (q),27.8 (t), 48.0 (t), 102.7 (s), 109.3 (s), 112.4 (d), 126.7 (2×d), 128.1(s), 128.2 (2×d), 129.2 (2×d), 129.5 (2×d), 130.6 (s), 130.7 (s), 133.8(d), 138.3 (d), 136.1 (s), 137.5 (s), 141.3 (s), 156.3 (s), 158.3 (s),163.4 (s). Anal calcd for C₂₆H₂₃N₃O₄S: C, 65.94; H, 4.90; N, 8.87.Found: C, 65.82; H, 5.01; N, 8.74.

7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP089). This compound was obtained by reaction of PP079 with ammoniumcarbonate. Green solid; yield: 52%; m.p.: 218-219° C.; IR: 3609 (NH),3583-3567 (NH₂), 1709 (CO), 1651 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 2.11(3H, s, CH₃), 2.44-2.56 (2H, m, CH₂), 2.77-2.82 (2H, m, CH₂), 6.02 (2H,s, CH₂), 6.84 (2H, d, J=8.0 Hz, H-3′ e H-5′), 6.92 (2H, d, J=8.0 Hz,H-2′ e H-6′), 7.53-7.73 (5H, m, H-3″, H-4″, H-5″ e NH₂), 7.87 (2H, d,J=6.1 Hz, H-2″ e H-6″), 8.03 (1H, s, H-6), 11.84 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 20.6 (q), 26.8 (t), 29.3 (t), 40.4 (d), 48.2 (t), 97.3(s), 117.3 (s), 122.9 (s), 125.0 (s), 126.7 (2×d), 127.8 (2×d), 128.8(2×d), 129.0 (2×d), 131.2 (s), 133.7 (d), 135.8 (s), 136.4 (d), 140.7(s), 141.1 (s), 145.9 (s), 158.5 (s), 159.7 (s), 162.0 (s). Anal calcdper C₂₆H₂₂BrN₃O₄S: C, 56.53; H, 4.01; N, 7.61. Found: C, 56.38; H, 4.31;N, 7.46.

N,7-di(benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-JH-pyrrolo[3,2-h]quinoline-2-carboxamide(PP100). This compound was obtained by reaction of PP081 withbenzenesulfonamide. Yellow solid; yield: 56%; m.p.: 122-123° C.; IR:3610 (NH), 3588 (NH), 1680 (CO), 1652 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):2.08 (3H, s, CH₃), 2.61 (2H, t, J=6.5 Hz, CH₂), 2.91 (2H, t, J=6.5 Hz,CH₂), 6.97 (2H, s, CH₂), 6.51 (1H, d, J=6.8 Hz, Ar), 6.65 (1H, s, Ar),6.93 (2H, d, J=6.1 Hz, Ar), 7.53-7.70 (6H, m, Ar), 7.86-7.94 (5H, m, Arand NH), 8.15 (1H, s, H-6), 12.01 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):20.5 (q), 21.4 (t), 27.00 (t), 48.6 (t), 105.3 (s), 124.1 (s), 124.0(d), 126.0 (s), 126.5 (s), 127.6 (s), 127.7 (s), 127.8 (2×d), 127.9 (d),128.3 (d), 128.4 (2×d), 128.5 (s), 128.6 (d), 128.7 (d), 129.4 (2×d),129.5 (2×d), 133.8 (s), 133.9 (s), 134.0 (d), 137.9 (d), 138.4 (s),138.8 (s), 141.1 (s), 158.4 (s). Anal calcd for C₃₂H₂₆BrN₃O₆S₂: C,55.49; H, 3.78; N, 6.07. Found: C, 55.61; H, 3.63; N, 6.19.

7-(Benzenesulfonyl)-3-bromo-N-tert-butyl-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP101). This compound was obtained by reaction of PP081 witht-butylamine. White solid; yield: 59%; m.p.: 216-217° C.; IR: 3381 (NH),3315 (NH), 1700 (CO), 1684 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.28 (9H,s, 3×CH₃), 2.16 (3H, s, CH₃), 2.59 (2H, t, J=6.3 Hz, CH₂), 2.88 (2H, t,J=6.3 Hz, CH₂), 6.04 (2H, s, CH₂), 6.89-7.09 (4H, m, H-2′, H-4′, H-5′and H-6′), 7.53-7.69 (3H, m, H-3″, H-4″ and H-5″), 7.93-7.99 (3H, m,H-2″, H-6″ and NH), 8.10 (1H, s, H-6), 11.91 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 20.7 (q), 21.4 (t), 27.2 (t), 28.7 (3×q), 48.7 (t),55.4 (s), 97.4 (s), 111.0 (s), 117.0 (s), 123.3 (s), 125.0 (d), 127.5(d), 128.2 (d), 128.3 (2×d), 128.6 (d), 128.7 (s), 129.5 (2×d), 132.6(s), 133.8 (d), 137.7 (d), 138.3 (s), 138.8 (s), 141.3 (s), 151.0 (s),158.5 (s), 159.9 (s). Anal calcd for C₃₀H₃₀BrN₃O₄S: C, 59.21; H, 4.97;N, 6.91. Found: C, 65.81; H, 5.04; N, 9.03.

7-(Benzenesulfonyl)-3-bromo-N-(5-tert-butyl-1,2-oxazol-3-yl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP102). This compound was obtained by reaction of PP081 with5-tert-butylisoxazol-3-amine. White solid; yield: 50%; m.p.: 202-203°C.; IR: 3353 (NH), 3289 (NH), 1695 (CO), 1677 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.23 (9H, s, 3×CH₃), 2.20 (3H, s, CH₃), 2.62 (2H, t,J=6.5 Hz, CH₂), 2.94 (2H, t, J=6.5 Hz, CH₂), 6.14 (2H, s, CH₂),6.80-6.86 (2H, m, Ar), 7.00-7.15 (2H, m, Ar), 7.58-7.69 (4H, m, H-3″,H-4″, H-5″ and CH-isoxazole), 7.93-7.95 (3H, m, H-2″, H-6″ and NH), 8.14(1H, s, H-6), 11.88 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 20.4 (q), 21.4(t), 27.1 (t), 29.5 (3×q), 36.3 (s), 49.3 (t), 96.2 (s), 101.6 (d),117.0 (s), 123.1 (s), 125.0 (d), 126.6 (s), 126.9 (s), 128.3 (2×d),128.4 (d), 128.5 (d), 128.8 (d), 129.5 (2×d), 131.1 (s), 133.8 (d),137.7 (s), 137.9 (d), 138.3 (s), 138.6 (s), 141.3 (s), 151.0 (s), 158.5(s), 161.8 (s), 162.8 (s). Anal calcd for C₃₃H₃₁BrN₄O₅S: C, 58.67; H,4.63; N, 8.29. Found: C, 58.81; H, 4.49; N, 8.41.

General Procedure for the Synthesis of Compound of Type 13

To a solution of the suitable tricyclic derivatives of type 9 (0.22mmol) in anhydrous DMF (20 mL), potassium hydroxide was added and thereaction mixture was stirred at room temperature. After 15 min. iodine(0.056 g, 0.22 mmol) was added and the reaction mixture was heated at40° C. for 24 h. After cooling, the reaction mixture was poured ontocrushed ice. The precipitate was filtered off, dried and purified bychromatography (DCM).

Ethyl1-(4-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-8,9-dihydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(13, PP058). This product was obtained by reaction of PP007. Dark yellowsolid; yield: 50%; m.p.: 197-198° C.; IR: 3348 (NH), 1713 (CO), 1669(CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.39 (2H, t, J=7.1 Hz, CH₃), 2.31 (3H,s, CH₃), 4.38 (2H, q, J=7.1 Hz, CH₂), 6.10 (2H, s, CH₂), 7.04 (2H, d,J=7.9 Hz, H-2′ and H-6′), 7.19 (2H, d, J=7.9 Hz, H-3′ and H-5′), 7.28(1H, s, H-7), 7.39-7.59 (6H, m, Ar), 8.10-8.13 (2H, m, Ar), 9.10 (1H, s,NH); ¹³C nmr (CDCl₃) (ppm): 14.2 (q), 21.2 (q), 49.8 (t), 61.5 (t),111.9 (d), 115.2 (s), 118.5 (d), 122.9 (d), 125.4 (s), 125.6 (2×d),128.4 (s), 128.8 (2×d), 129.1 (2×d), 130.0 (s), 130.8 (2×d), 131.0 (s),131.8 (s), 132.5 (s), 133.6 (d), 138.7 (s), 139.5 (s), 145.5 (d), 156.3(s), 161.1 (s). Anal calcd for C₂₈H₂₄N₂O₅S: C, 67.18; H, 4.83; N, 5.60.Found: C, 67.30; H, 4.71; N, 5.49.

The following additional compounds were prepared according to syntheticschemes 1 and 2 (PP001-7, 9-13, 26, 38-47, 49-54), as reported inBarraja P, et al. Bioorg Med Chem 2010, 18, 4830-4843; Spanò V, et al.Eur J Med Chem 2017, 128, 300-318.

CPD R R¹ R² R³ n PP001(#) SO₂Ph H — SO₂Ph 1 PP002(#) H H — SO₂Ph 1PP003(#) SO₂Ph H — CN 1 PP004(#) Me H — SO₂Ph 1 PP005(#) Bn H — SO₂Ph 1PP006(#) Ph H — SO₂Ph 1 PP007(#) 4-MeBn COOEt — SO₂Ph 1 PP009(#) H COOEt— SO₂Ph 1 PP010(#) Me COOEt — SO₂Ph 1 PP011(#) Bn COOEt — SO₂Ph 1PP012(#) 4-MeBn H — SO₂Ph 1 PP013(#) 4-MeOBn COOEt — SO₂Ph 1 PP026(#)4-MeOBn H — SO₂Ph 1 PP038(#) Me H — SO₂Ph 2 PP039(#) Bn H — SO₂Ph 2PP040(#) 2-OMeBn H — SO₂Ph 2 PP041(#) 3-OMeBn H — SO₂Ph 2 PP042(#)4-OMeBn H — SO₂Ph 2 PP043(#) Me COOEt — SO₂Ph 2 PP044(#) Bn COOEt —SO₂Ph 2 PP045(#) 2-OMeBn COOEt — SO₂Ph 2 PP046(#) 3-OMeBn COOEt — SO₂Ph2 PP047(#) 4-OMeBn COOEt — SO₂Ph 2 PP049(§) Me H — SO₂Ph 2 PP050(§) MeCOOEt — SO₂Ph 2 PP051(*) Me H — SO₂Ph 2 PP052(*) 4-OMeBn H — SO₂Ph 2PP053(*) Me COOEt — SO₂Ph 2 PP054(*) 4-OMeBn COOEt — SO₂Ph 2(#)Compounds of formula 9 in Scheme 2; (§)Compounds of formula 10 inScheme 2; (*)Compounds of formula 11 in Scheme 2; ({circumflex over( )}) Compounds of formula 12 in Scheme 2

Scheme 3 describes the general synthesis of pyrrolo[3,2-h]quinazolinesof formulas 15-18, as reported in Table 3. The synthetic procedure ofScheme 3 is particularly preferred for compounds where R¹ is an estersuch as COOEt and R² is a halogen atom such as Br. Annelation of thepyrimidine ring to the cyclohexapyrrole scaffold bearing the decorationof the best candidates of type 9 was achieved by reacting theenaminoketones 8 with guanidine nitrate in the presence of sodiummethoxide (MeONa) as the base, to obtain the 2-amino substitutedpyrrolo[3,2-h]quinazolines 15 (Scheme 3). The latter were sulphonylatedat the amino group generating compounds 16. Both 15 and 16 were thenbrominated at the pyrrole ring furnishing the corresponding bromoderivatives 17 and 18 (Scheme 3).

The derivatives reported in Table 3 below are exemplary compounds thatmay be prepared according to the synthetic procedure of Scheme 3.Relative additivity indeces (AI %), which were measured as described inthe Materials and Methods section, are also reported.

TABLE 3 Pyrrolo[3,2-h]quinazolines of formula:

CPD R R¹ R² R^(a) AI^(a) SVQ4  3-MeBn COOEt Br H  4% SVQ9  4-MeBn COOEtH SO₂Ph  98% SVQ10 4-MeBn COOEt Br SO₂Ph 134% SVQ11 3-MeBn COOEt H SO₂Ph151% SVQ12 3-MeBn COOEt Br SO₂Ph 152% SVQ13 3,4-(Me)₂Bn COOEt H SO₂Ph 86% SVQ14 3,4-(Me)₂Bn COOEt Br SO₂Ph 128% SVQ15 4-BrBn COOEt H SO₂Ph100% SVQ16 4-BrBn COOEt Br SO₂Ph  98% ^(a)Activity of compounds (at 10μM) was expressed as additivity index (AI %) which is calculated as(QR_(TOT)-QR_(VX))/QR_(VX) where QR_(TOT) is the quenching rate (HS-YFPassay) in the presence of test compound plus VX-809 and QR_(VX) is thequenching rate with VX-809 alone).

A detailed description of the synthesis of exemplary compounds producedaccording to Scheme 3 is provided hereinbelow.

General Procedure for the Synthesis of Compounds of Type 15

To a suspension of MeONa (1.08 g, 20 mmol) in anhydrous ethanol (15 mL),guanidine nitrate (1.22 g, 10 mmol) and a solution of the suitableenaminoketons of type 8 (2 mmol) in anhydrous ethanol (20 mL) wereadded. The reaction mixture was heated at reflux up to completeness.Then the reaction mixture was poured onto crushed ice and theprecipitate was filtered off, dried and purified by chromatography(DCM/AcOEt 9:1).

Ethyl2-amino-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ1). This compound was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylateafter 6 h. White solid; yield: 85%; m.p.: 171-172° C.; IR: 3416-3313(NH₂), 1699 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.23 (3H, t, J=7.1 Hz,CH₃), 2.20 (3H, s, CH₃), 2.64 (4H, s, 2×CH₂), 4.18 (2H, q, J=7.1 Hz,CH₂), 6.37-6.43 (4H, m, CH₂ and NH₂), 6.84 (1H, s, H-3), 6.90 (2H, d,J=8.0 Hz, H-3′ and H-5′), 7.03 (2H, d, J=8.0 Hz, H-2′ and H-6′), 8.05(1H, s, H-6); ¹³C nmr (DMSO-d₆) (ppm): 14.1 (q), 20.5 (q), 21.1 (t),24.3 (t), 48.1 (t), 59.8 (t), 115.8 (d), 116.5 (s), 125.0 (s), 126.3(2×d), 127.3 (s), 128.8 (2×d), 130.5 (s), 135.8 (s), 136.5 (s), 154.7(s), 156.0 (d), 160.2 (s), 161.9 (s). Anal calcd for C₂₁H₂₂N₄O₂: C,69.59; H, 6.12; N, 15.46. Found: C, 69.78; H, 6.01; N, 15.32.

Ethyl2-amino-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ3). This compound was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-(3-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylateafter 3 h. Brown solid; yield: 92%; m.p.: 149-150° C.; IR: 3461-3416(NH₂), 1697 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.23 (3H, t, J=7.0 Hz,CH₃), 2.20 (3H, s, CH₃), 2.65 (4H, s, 2×CH₂), 4.18 (2H, q, J=7.0 Hz,CH₂), 6.42 (4H, s, CH₂ and NH₂), 6.69-7.14 (5H, m, H-3, H-2′, H-4′, H-5′and H-6′), 8.05 (1H, s, H-6); ¹³C nmr (DMSO-d₆) (ppm): 14.1 (q), 21.0(q), 21.1 (t), 24.3 (t), 48.4 (t), 59.8 (t), 115.9 (d), 123.2 (d), 125.0(s), 126.9 (d), 127.2 (s), 127.3 (d), 128.2 (d), 130.7 (s), 137.1 (s),139.5 (s), 154.7 (s), 156.2 (d), 160.4 (s), 162.1 (s). Anal calcd forC₂₁H₂₂N₄O₂: C, 69.59; H, 6.12; N, 15.46. Found: C, 69.46; H, 6.24; N,15.32.

Ethyl2-amino-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ5). This compound was obtained by reaction of ethyl6-[(dimethylamino)methylidene]-1-[(3,4-dimethylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylateafter 2 h. White solid; yield: 82%; m.p.: 157-158° C.; IR: 3513-3410(NH₂), 1703 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.24 (3H, t, J=7.0 Hz,CH₃), 2.10 (6H, s, 2×CH₃), 2.64 (4H, s, 2×CH₂), 4.19 (2H, q, J=7.0 Hz,CH₂), 6.38-6.42 (4H, m, CH₂ e NH₂), 6.65 (1H, d, J=7.6 Hz, H-6′), 6.79(1H, s, H-2′), 6.83 (1H, s, H-3), 6.96 (1H, d, J=6.5 Hz, H-5′), 8.05(1H, s, H-6); ¹³C nmr (DMSO-d₆) (ppm): 14.1 (q), 18.9 (q), 19.5 (q),20.1 (t), 24.3 (t), 48.1 (t), 59.8 (t), 115.8 (d), 116.4 (s), 123.6 (d),124.9 (s), 127.1 (d), 127.6 (s), 129.3 (d), 130.6 (s), 134.5 (s), 135.7(s), 136.8 (s), 154.6 (s), 156.1 (d), 160.2 (s), 161.9 (s). Anal calcdfor C₂₂H₂₄N₄O₂: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.07; H, 6.56;N, 15.01.

Ethyl2-amino-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ7). This compound was obtained by reaction of ethyl1-[(4-bromophenyl)methyl]-6-[(dimethylamino)methylidene]-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylateafter 5 h. White solid; yield: 74%; m.p.: 168-169° C.; IR: 3513-3410(NH₂), 1697 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.23 (3H, t, J=7.0 Hz,CH₃), 2.66 (4H, s, 2×CH₂), 4.18 (2H, q, J=7.0 Hz, CH₂), 6.35-6.42 (4H,m, CH₂ and NH₂), 6.87 (1H, s, H-3), 6.98 (2H, d, J=8.3 Hz, H-2′ andH-6′), 7.44 (2H, d, J=8.3 Hz, H-3′ and H-5′), 8.06 (1H, s, H-6); ¹³C nmr(DMSO-d₆) (ppm): 14.1 (q), 21.1 (t), 24.3 (t), 48.1 (t), 59.9 (t), 115.9(d), 116.5 (s), 119.8 (s), 124.8 (s), 127.4 (s), 128.6 (2×d), 130.4 (s),131.1 (2×d), 138.9 (s), 154.4 (s), 156.2 (d), 160.1 (s), 161.9 (s). Analcalcd for C₂₀H₁₉BrN₄O₂: C, 56.22; H, 4.48; N, 13.11. Found: C, 56.10; H,4.51; N, 12.98.

General Procedure for the Synthesis of Compounds of Type 16

To a solution of suitable tricyclic compounds of type 15 (0.67 mmol) inanhydrous pyridine (1.8 mL), benzensulfonyl chloride (0.17 mL, 1.3 mmol)was added and the reaction mixture was stirred at room temperature for24 h. Then the reaction mixture was poured onto crushed ice and theprecipitate was filtered off, dried and purified by chromatography(DCM/AcOEt 95:5).

Ethyl2-[(benzenesulfonyl)amino]-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ9). This compound was obtained by reaction of SVQ1. White solid;yield: 82%; m.p.: 218-219° C.; IR: 3422 (NH), 1709 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.22 (3H, t, J=7.1 Hz, CH₃), 2.20 (3H, s, CH₃), 2.69(4H, s, 2×CH₂), 4.18 (2H, q, J=7.1 Hz, CH₂), 6.31 (2H, s, CH₂),6.77-6.84 (3H, m, H-3, H-3′ and H-5′), 7.01 (2H, d, J=7.9 Hz, H-2′ andH-6′), 7.48-7.56 (3H, m, H-3″, H-4″ and H-5″), 7.86 (2H, d, J=7.1 Hz,H-2″ and H-6″), 8.26 (1H, s, H-6), 11.82 (1H, s, NH); ¹³C nmr (DMSO-d₆)(ppm): 14.6 (q), 20.0 (t), 21.5 (q), 24.8 (t), 48.7 (t), 60.5 (t), 116.4(d), 117.3 (s), 124.0 (s), 125.7 (2×d) 128.0 (2×d), 128.1 (2×d), 129.9(2×d), 131.0 (d), 135.2 (s), 136.4 (s), 136.5 (s), 137.3 (s), 155.3 (d),156.4 (s), 160.0 (s), 161.1 (s), 162.2 (s). Anal calcd for C₂₇H₂₆N₄O₄S:C, 64.52; H, 5.21; N, 11.15. Found: C, 64.65; H, 5.09; N, 11.02.

Ethyl2-[(benzenesulfonyl)amino]-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ11). This compound was obtained by reaction of SVQ3. Yellow solid;yield: 92%; m.p.: 201-202° C.; IR: 3399 (NH), 1709 (CO) cm¹; ¹H nmr(DMSO-d₆) (ppm): 1.21 (3H, t, J=7.0 Hz, CH₃), 2.19 (3H, s, CH₃), 2.69(4H, s, 2×CH₂), 4.17 (2H, q, J=7.0 Hz, CH₂), 6.33 (2H, s, CH₂), 6.62(1H, d, J=7.5 Hz, Ar), 6.78-6.85 (2H, m, H-3 and Ar), 6.94-7.12 (2H, m,Ar), 7.44-7.56 (3H, m, H-3″, H-4″ and H-5″), 7.81 (2H, d, J=6.5 Hz, H-2″and H-6″), 8.26 (1H, s, H-6), 11.81 (1H, s, NH); ¹³C nmr (DMSO-d₆)(ppm): 13.0 (q), 20.4 (t), 20.0 (q), 24.2 (t), 48.4 (t), 60.1 (t), 115.9(d), 122.0 (s), 122.8 (d), 122.9 (s), 126.6 (2×d), 126.7 (d), 127.3 (d),128.2 (d), 128.9 (2×d), 129.6 (s), 132.6 (d), 137.1 (s), 139.4 (s),140.2 (s), 140.8 (s), 154.5 (d), 155.1 (s), 155.3 (s), 160.0 (s). Analcalcd for C₂₇H₂₆N₄O₄S: C, 64.52; H, 5.21; N, 11.15. Found: C, 64.40; H,5.33; N, 11.02.

Ethyl2-[(benzenesulfonyl)amino]-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ13). This compound was obtained by reaction of SVQ5. Pale yellowsolid; yield: 73%; m.p.: 239-240° C.; IR: 3371 (NH), 1703 (CO) cm⁻¹; ¹Hnmr (DMSO-d₆) (ppm): 1.22 (3H, t, J=7.1 Hz, CH₃), 2.09 (3H, s, CH₃),2.11 (3H, s, CH₃), 2.68 (4H, s, 2×CH₂), 4.18 (2H, q, J=7.1 Hz, CH₂),6.29 (2H, s, CH₂), 6.53 (1H, d, J=7.5 Hz, H-6′), 6.75 (1H, s, H-3), 6.84(1H, s, H-2′), 6.94 (1H, d, J=7.5 Hz, H-5′), 7.44-7.56 (3H, m, H-3″,H-4″ and H-5″), 7.86 (2H, d, J=6.8 Hz, H-2″ and H-6″), 8.26 (1H, s,H-6), 11.81 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.1 (q), 18.9 (q),19.5 (q), 20.4 (t), 24.3 (t), 48.0 (t), 60.1 (t), 115.9 (d), 121.9 (s),122.0 (s), 123.2 (d), 126.7 (2×d), 127.4 (d), 128.9 (2×d), 129.3 (d),129.6 (s), 132.6 (d), 134.5 (s), 135.7 (s), 136.8 (s), 140.8 (s), 153.1(s), 154.5 (d), 155.1 (s), 155.3 (s), 160.0 (s). Anal calcd forC₂₈H₂₈N₄O₄S: C, 65.10; H, 5.46; N, 10.85. Found: C, 65.23; H, 5.32; N,10.80.

Ethyl2-[(benzenesulfonyl)amino]-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ15). This compound was obtained by reaction of SVQ7. White solid;yield: 79%; m.p.: 208-209° C.; IR: 3399 (NH), 1709 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.21 (3H, t, J=7.0 Hz, CH₃), 2.70 (4H, s, 2×CH₂), 4.18(2H, q, J=7.0 Hz, CH₂), 6.31 (2H, s, CH₂), 6.77-6.89 (3H, m, H-3 andAr), 7.41-7.52 (5H, m, Ar), 7.83 (2H, d, J=6.0 Hz, Ar), 8.27 (1H, s,H-6), 11.82 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.0 (q), 20.4 (t),24.2 (t), 47.9 (t), 60.2 (t), 116.1 (d), 119.8 (s), 122.0 (s), 122.1(s), 126.4 (s), 128.6 (2×d), 128.2 (2×d), 128.9 (2×d), 129.4 (s), 131.1(2×d), 132.6 (d), 138.8 (s), 140.7 (s), 149.0 (s), 155.0 (d), 155.1 (s),159.8 (s). Anal calcd for C₂₆H₂₃BrN₄O₄S: C, 55.03; H, 4.09; N, 9.87.Found: C, 55.26; H, 3.98; N, 9.76.

General Procedure for the Synthesis of Compounds of Type 17 and 18

To a solution of suitable tricyclic compounds of type 15 or 16 (0.22mmol) in anhydrous DCM (20 ml), Br₂ (0.44 mmol, 0.02 mL) was added at 0°C. and the reaction mixture was stirred at room temperature for 24 h.Then the reaction mixture was evaporated under reduced pressure. Thecrude was purified by chromatography (DCM/AcOEt 95:5).

Ethyl2-amino-7-bromo-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ2). This compound was obtained by reaction of SVQ1. White solid;yield: 87%; m.p.: 140-141° C.; IR: 3608-3586 (NH₂), 1664 (CO) cm⁻¹; ¹Hnmr (DMSO-d₆) (ppm): 1.25 (3H, t, J=7.1 Hz, CH₃), 2.21 (3H, s, CH₃),2.60-2.70 (4H, m, 2×CH₂), 4.26 (2H, q, J=7.1 Hz, CH₂), 6.41 (2H, s, CH₂)6.51 (2H, s, NH₂), 6.89 (2H, d, J=8.0 Hz, H-3′ and H-5′), 7.05 (2H, d,J=8.0 Hz, H-2′ and H-6′), 8.11 (1H, s, H-6); ¹³C nmr (DMSO-d₆) (ppm):13.9 (q), 20.4 (t), 20.6 (q), 23.6 (t), 49.0 (t), 60.6 (t), 103.7 (s),116.5 (s), 123.2 (s), 126.3 (2×d), 126.5 (s), 127.8 (s), 128.9 (2×d),129.7 (s), 136.0 (s), 153.9 (s), 156.8 (d), 159.5 (s), 161.9 (s). Analcalcd for C₂₁H₂₁BrN₄O₂: C, 57.15; H, 4.80; N, 12.70. Found: C, 57.02; H,4.92; N, 12.57.

Ethyl2-amino-7-bromo-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ4). This compound was obtained by reaction of SVQ3. Yellow solid;yield: 60%; m.p.: 119-120° C.; IR: 3307-3193 (NH₂), 1697 (CO)cm⁻¹; ¹Hnmr (DMSO-d₆) (ppm): 1.23 (3H, t, J=7.0 Hz, CH₃), 2.58-2.72 (4H, m,2×CH₂), 4.22 (2H, q, J=7.0 Hz, CH₂), 6.43 (2H, s, CH₂), 6.49 (2H, s,NH₂), 6.71 (1H, d, J=7.6 Hz, Ar), 6.88 (1H, s, H-2′), 7.01 (1H, d, J=7.6Hz, Ar), 7.12 (1H, t, J=7.6 Hz, H-5′), 8.11 (1H, s, H-6); ¹³C nmr(DMSO-d₆) (ppm): 14.4 (q), 20.8 (t), 21.5 (q), 24.1 (t), 49.8 (t), 61.0(t), 104.2 (s), 107.0 (s), 123.7 (d), 123.8 (s), 127.5 (d), 128.1 (d),128.3 (s), 128.8 (d), 130.2 (s), 137.8 (s), 139.4 (s), 154.5 (s), 157.1(d), 160.0 (s), 162.4 (s). Anal calcd for C₂₁H₂₁BrN₄O₂: C, 57.15; H,4.80; N, 12.70. Found: C, 57.02; H, 4.93; N, 12.62.

Ethyl2-amino-7-bromo-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ6). This compound was obtained by reaction of SVQ5. Yellow solid;yield: 78%; m.p.: 244-245° C.; IR: 3296-3188 (NH₂), 1703 (CO) cm⁻¹; ¹Hnmr (DMSO-d₆) (ppm): 1.25 (3H, t, J=7.0 Hz, CH₃), 2.12 (6H, s, 2×CH₃),2.69-2.77 (4H, m, 2×CH₂), 4.27 (2H, q, J=7.0 Hz, CH₂), 6.26 (2H, s,CH₂), 6.68 (1H, d, J=6.5 Hz, H-6′), 6.88 (1H, s, H-2′), 6.99 (1H, d,J=6.5 Hz, H-5′), 8.04 (2H, s, NH₂), 8.19 (1H, s, H-6); ¹³C nmr (DMSO-d₆)(ppm): 13.8 (q), 18.9 (q), 19.4 (q), 20.1 (t), 23.2 (t), 49.3 (t), 61.8(t), 103.2 (s), 117.0 (s), 123.7 (d), 126.9 (s), 127.4 (s), 127.7 (d),129.5 (d), 132.6 (s), 135.1 (s), 135.6 (s), 136.1 (s), 144.4 (d), 155.4(s), 159.0 (s), 159.3 (s). Anal calcd for C₂₂H₂₃BrN₄O₂: C, 58.03; H,5.09; N, 12.30. Found: C, 58.26; H, 4.97; N, 12.17.

Ethyl2-amino-7-bromo-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ8). This compound was obtained by reaction of SVQ7. Brown solid;yield: 69%; m.p.: 174-175° C.; IR: 3519-3416 (NH₂), 1703 (CO) cm⁻¹; ¹Hnmr (DMSO-d₆) (ppm): 1.24 (3H, t, J=7.0 Hz, CH₃), 2.58-2.73 (4H, m,2×CH₂), 4.24 (2H, q, J=7.0 Hz, CH₂), 6.39 (2H, s, CH₂), 6.66 (2H, s,NH₂), 6.97 (2H, d, J=8.3 Hz, H-2′ and H-6′), 7.47 (2H, d, J=8.3 Hz, H-3′and H-5′), 8.12 (1H, s, H-6); ¹³C nmr (DMSO-d₆) (ppm): 13.9 (q), 23.7(t), 27.6 (t), 49.6 (t), 61.3 (t), 99.1 (s), 112.5 (s), 122.8 (s), 127.4(s), 128.7 (2×d), 129.8 (s), 131.2 (2×d), 132.5 (s), 134.4 (s), 144.9(d), 156.8 (s), 159.9 (s), 162.9 (s). Anal calcd for C₂₀H₁₈Br₂N₄O₂: C,47.46; H, 3.58; N, 11.07. Found: C, 47.62; H, 3.41; N, 10.94.

Ethyl2-[(benzenesulfonyl)amino]-7-bromo-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ10). This compound was obtained by reaction of SVQ9. Pale yellowsolid; yield: 80%; m.p.: 221-222° C.; IR: 3604 (NH), 1703 (CO) cm⁻¹; ¹Hnmr (DMSO-d₆) (ppm): 1.23 (3H, t, J=7.1 Hz, CH₃), 2.21 (3H, s, CH₃),2.51 (2H, t, J=7.0 Hz, CH₂), 2.78 (2H, t, J=7.0 Hz, CH₂), 4.21 (2H, q,J=7.1 Hz, CH₂), 6.30 (2H, s, CH₂), 6.76 (2H, d, J=7.8 Hz, H-3′ andH-5′), 7.03 (2H, d, J=7.8 Hz, H-2′ and H-6′), 7.47-7.56 (3H, m, H-3″,H-4″ and H-5″), 7.85 (1H, d, J=7.1 Hz, H-2″ and H-6″), 8.33 (1H, s,H-6), 11.86 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 13.9 (q), 19.8 (t),20.6 (q), 23.6 (t), 49.0 (t), 60.8 (t), 103.7 (s), 122.3 (s), 124.7 (s),126.0 (d), 126.7 (d), 128.7 (s), 128.9 (d), 129.0 (d), 129.3 (s), 132.7(d), 135.9 (s), 136.1 (s), 140.5 (s), 154.4 (s). 155.2 (s), 156.1 (d),159.3 (s). Anal calcd for C₂₇H₂₅BrN₄O₄S: C, 55.77; H, 4.33; N, 9.64.Found: C, 55.64; H, 4.43; N, 9.77.

Ethyl2-[(benzenesulfonyl)amino]-7-bromo-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ12). This compound was obtained by reaction of SVQ11. White solid;yield: 78%; m.p.: 237-238° C.; IR: 3387 (NH), 1703 (CO) cm¹; ¹H nmr(DMSO-d₆) (ppm): 1.21 (3H, t, J=7.0 Hz, CH₃), 2.20 (3H, s, CH₃),2.60-2.63 (2H, m, CH₂), 2.75-2.78 (2H, m, CH₂), 4.20 (2H, q, J=7.0 Hz,CH₂), 6.32 (2H, s, CH₂), 6.60 (1H, d, J=7.3 Hz, Ar), 6.79 (1H, s, H-2′),6.97-7.14 (2H, m, Ar), 7.43-7.55 (3H, m, H-3″, H-4″ and H-5″), 7.85 (2H,d, J=7.1 Hz, H-2″ and H-6″), 8.33 (1H, s, H-6), 11.87 (1H, s, NH); ¹³Cnmr (DMSO-d₆) (ppm): 13.9 (q), 19.8 (t), 21.0 (q), 23.6 (t), 49.3 (t),60.8 (t), 103.6 (s), 122.3 (s), 122.9 (d), 124.7 (s), 126.7 (2×d), 126.8(d), 127.6 (d), 128.3 (d), 128.7 (s), 128.9 (d), 129.2 (2×d), 132.7 (d),137.3 (s), 138.8 (s), 140.5 (s), 154.4 (s), 155.1 (s), 159.3 (s), 160.6(s). Anal calcd for C₂₇H₂₅BrN₄O₄S: C, 55.77; H, 4.33; N, 9.64. Found: C,55.91; H, 4.21; N, 9.53.

Ethyl2-[(benzenesulfonyl)amino]-7-bromo-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ14). This compound was obtained by reaction of SVQ13. Orange solid;yield: 68%; m.p.: 224-225° C.; IR: 3399 (NH), 1700 (CO) cm¹; ¹H nmr(DMSO-d₆) (ppm): 1.24 (3H, t, J=7.0 Hz, CH₃), 2.11 (3H, s, CH₃), 2.13(3H, s, CH₃), 2.72-2.83 (4H, m, 2×CH₂), 4.23 (2H, q, J=7.0 Hz, CH₂),6.25 (2H, s, CH₂), 6.53 (1H, d, J=6.4 Hz, H-6′), 6.75 (1H, s, H-2′),6.97 (1H, d, J=6.4 Hz, H-5′), 7.43-7.57 (3H, m, H-3″, H-4″ and H-5″),7.85 (2H, d, J=6.6 Hz, H-2″ and H-6″), 8.35 (1H, s, H-6); ¹³C nmr(DMSO-d₆) (ppm): 14.3 (q), 19.4 (q), 19.9 (q), 20.3 (t), 24.1 (t), 49.5(t), 61.3 (t), 104.0 (s), 123.9 (d), 127.2 (2×d), 128.0 (d), 129.5(2×d), 130.0 (d), 120.7 (s), 129.0 (s), 129.2 (s), 133.4 (d), 135.4 (s),135.5 (s), 136.4 (s), 136.7 (s), 140.6 (s), 152.7 (d), 153.9 (s), 155.6(s), 159.9 (s). Anal calcd for C₂₈H₂₇BrN₄O₄S: C, 56.47; H, 4.57; N,9.41. Found: C, 56.59; H, 4.36; N, 9.29.

Ethyl2-[(benzenesulfonyl)amino]-7-bromo-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ16). This compound was obtained by reaction of SVQ15. White solid;yield: 76%; m.p.: 204-205° C.; IR: 3393 (NH), 1700 (CO) cm¹; ¹H nmr(DMSO-d₆) (ppm): 1.21 (3H, t, J=7.1 Hz, CH₃), 2.62 (2H, t, J=6.7 Hz,CH₂), 2.80 (2H, t, J=6.7 Hz, CH₂), 4.21 (2H, q, J=7.1 Hz, CH₂), 6.31(2H, s, CH₂), 6.85 (2H, d, J=8.3 Hz, Ar), 7.42-7.57 (5H, m, Ar), 7.81(2H, d, J=8.3 Hz, Ar), 8.35 (1H, s, H-6), 11.86 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 13.9 (q), 19.8 (t), 23.5 (t), 60.8 (t), 103.9 (s),120.0 (s), 124.3 (s), 126.6 (2×d),128.3 (2×d), 128.6 (s), 129.0 (2×d),129.4 (s), 131.2 (2×d), 132.9 (d), 138.3 (s), 139.2 (s), 140.5 (s),149.7 (s), 155.1 (s), 156.1 (d), 159.2 (s). Anal calcd forC₂₆H₂₂Br₂N₄O₄S: C, 48.31; H, 3.43; N, 8.67. Found: C, 48.19; H, 3.55; N,8.54. Ethyl and isopropyl pyrrole-2-carboxyesters 20a and 20brespectively can be synthesized by reaction of trichloroacetyl pyrrole19 in the presence of potassium ethoxide in ethanol or potassiumcarbonate in isopropanol (Scheme 4). Alkylation at the pyrrole nitrogencarried out in the presence of NaH, KI and ethyl 4-bromobutyrate orethyl 5-bromovalerate gave compounds of formula 21 which were hydrolyzedin basic media to give the corresponding acids of formula 22. The latterwere cyclized into ketones of formula 23 in polyphosphoric acid(R²=COOEt) or trifluoroacetic anhydride (R²=COOiPr) and subsequentlyconverted into the key enaminoketones 24.

Scheme 5 describes the general synthesis ofpyrrolo[1,2-h][1,7]naphthyridinones (n=1),pyrido[2,3-c]pyrrolo[1,2-a]azepinones (n=2), pyrimido[5,4-g]indolizines(n=1) and pyrimido[4,5-c]pyrrolo[1,2-a]azepines (n=2) as reported inTables 4 and 5.

To obtain the new tricyclic systems of type 25, enaminoketones 24 werereacted with phenylsulfonylacetonitrile as dinucleophile in refluxingethanol (Scheme 5). Similarly to the previous class of pyridinecompounds 9, the new derivatives 25 were subjected to methylation in DMFin the presence of NaH and iodomethane as methylating agent (Scheme 5).A mixture of the O-methyl derivatives 26 and the N-methyl derivatives 27was isolated.

Moreover, bromination of the pyrrole ring was achieved in DCM and Br₂ asbrominating agent, leading to the bromo derivatives of formula 28 (Table4). Enaminones 24 were also reacted with guanidine nitrate or1-substituted guanidines in the presence of sodium methoxide to annelatethe pyrimidine ring into the basic scaffold leading to the tryciclicderivatives 29. The 2-amino derivatives were subsequently acetylatedwith acetyl chloride and trimethylamine to give compounds 30.

The derivatives reported in Tables 4 and 5 below are exemplary compoundsthat may be prepared according to the synthetic procedure of Schemes 4and 5. Relative additivity indeces (AI %), which were measured asdescribed in the Materials and Methods section, are also reported.

TABLE 4 Pyrrolo[1,2-h][1,7]naphthyridinones (n = 1) and pyrido[2,3-c]pyrrolo[1,2-a]azepinones (n = 2) CPD R² R¹ n AI (%)^(a) QZN2(@) COOEtBr 1  19% QZN5($) COOEt — 2  19% QZN6(@) COOEt Br 2 136% QZN10(@) COOiPrBr 1 101% QZN13($) COOiPr — 2  8% QZN14(@) COOiPr Br 2 141% ($)Compoundsof formula 25 in Scheme 4; (@)Compounds of formula 28 in Scheme 4^(a)Activity of compounds (at 10 μM) was expressed as additivity index(AI %) which is calculated as (QR_(TOT) − QR_(VX))/QR_(VX) whereQR_(TOT) is the quenching rate (HS-YFP assay) in the presence of testcompound plus VX-809 and QR_(VX) is the quenching rate with VX-809alone.

TABLE 5 Pyrimido[5,4-g]indolizines (n = 1) and pyrimido[4,5-c]pyrrolo[1,2-a]azepines (n = 2) of formula:

CPD R² R^(a) n AI (%) ^(a) QZQ14 COOEt cyclopentyl 1 18% QZQ20 COOiPrcyclopentyl 1  5% QZQ21 COOiPr H 2  6% QZQ26 COOiPr COMe 2  2% ^(a)Activity of compounds (at 10 μM) was expressed as additivity index (AI%) which is calculated as (QR_(TOT)-QR_(VX))/QR_(VX) where QR_(TOT) isthe quenching rate (HS-YFP assay) in the presence of test compound plusVX-809 and QR_(VX) is the quenching rate with VX-809 alone.

A detailed description of the synthesis of exemplary compounds producedaccording to Schemes 4 and 5 is provided hereinbelow.

Synthesis of propan-2-yl 1H-pyrrole-2-carboxylate 20

A suspension of K₂CO₃ (3.96 g) in 2-propanol (12 mL) was stirred at roomtemperature for 16 h. Then a solution of2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone 19 (1.5 g, 7.2 mmol) in2-propanol was added dropwise and the reaction mixture was heated at 60°C. for 1 h and 30 min. After cooling, the solvent was removed underreduced pressure. The residue was added with water and the solution wasacidified with HCl 6M and then extracted with ethyl acetate (1×40 mL).The organic phase was dried on Na₂SO₄ and the solvent was removed underreduced pressure to give the desired compound 20. Colorless oil; yield65%; IR: 1699 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.27 (6H, d, J=6.2 Hz,2×CH₃), 1.28 (3H, s, CH₃), 4.97-5.15 (1H, m, CH), 6.12-6.18 (1H, m, Ar),6.72-6.79 (1H, m, Ar), 6.97-7.02 (1H, m, Ar); ¹³C nmr (DMSO-d₆) (ppm):21.8 (2×q), 66.6 (d), 109.3 (d), 114.7 (d), 121.1 (s), 123.7 (d), 159.9(s), 171.9 (s). Anal calcd for C₈H₁₁NO₂: C, 62.73; H, 7.24; N, 9.14.Found: C, 62.87; H, 7.08; N, 8.99.

Synthesis of 1-Substituted pyrrole-2-carboxylate 21a,b

To a solution of ethyl 1H-pyrrole-2-carboxylate 20a (3.6 mmol) inanhydrous DMF (15 mL), NaH (7.2 mmol) was added at 0° C. and thereaction mixture was stirred at 40° C. for 3 h. After cooling, KI (0.64g, 4.0 mmol), ethyl 4-bromobutyrate or ethyl 5-bromovalerate (7.2 mmol)were added and the reaction mixture was heated at reflux for 16 h. Aftercooling, the reaction mixture was poured onto crushed ice and theaqueous solution was extracted with ethyl acetate (3×50 mL). The organiclayers were dried over Na₂SO₄ and the solvent removed under reducedpressure. The crude product was purified by chromatography column(Petroleum ether/AcOEt 9:1).

Ethyl 1-(4-ethoxy-4-oxobutyl)-1H-pyrrole-2-carboxylate (21a). Thiscompound was obtained by reaction of 20a with ethyl 4-bromobutyrate.Yellow oil; yield: 85%; IR: 1718 (CO), 1684 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.22-1.38 (6H, m, 2×CH₃), 2.02-2.16 (2H, m, CH₂), 2.28 (2H, t,J=6.8 Hz, CH₂), 4.07-4.41 (6H, m, 3×CH₂), 6.10-6.13 (1H, m, Ar),6.80-6.85 (1H, m, Ar), 6.94-6.96 (1H, m, Ar; ¹³C nmr (DMSO-d₆) (ppm):14.2 (q), 14.4 (q), 26.7 (t), 31.0 (t), 48.1 (t), 59.8 (t), 60.6 (t),108.0 (d), 118.2 (d), 121.9 (s), 128.8 (d), 161.1 (s), 172.9 (s). Analcalcd for C₁₃H₁₉NO₄: C, 61.64; H, 7.56; N, 5.53. Found: C, 61.51; H,7.69; N, 5.75.

Ethyl 1-(5-ethoxy-5-oxopentyl)-1H-pyrrole-2-carboxylate (21b). Thiscompound was obtained by reaction of 20a with ethyl 5-bromovalerate.Yellow oil; yield: 75%; IR: 1715 (CO), 1698 (CO) cm⁻¹; ¹H nmr (CDCl₃)(ppm): 1.21-1.38 (6H, m, 2×CH₃), 1.54-1.69 (2H, m, CH₂), 1.73-1.87 (2H,m CH₂), 2.31 (2H, t, J=7.3 Hz, CH₂), 4.06-4.35 (6H, m, 3×CH₂), 6.09-6.13(1H, m, Ar), 6.82-6.84 (1H, m, Ar), 6.94-6.97 (1H, m, Ar); ¹³C nmr(CDCl₃) (ppm): 14.2 (q), 14.4 (q), 22.0 (t), 31.0 (t), 33.8 (t), 48.8(t), 59.7 (t), 60.3 (t), 107.9 (d), 118.1 (d), 121.8 (s), 128.6 (d),161.1 (s), 173.3 (s). Anal calcd for C₁₄H₂₁NO₄: C, 62.90; H, 7.92; N,5.24. Found: C, 63.09; H, 7.84; N, 5.43.

Synthesis of 1-Substituted pyrrole-2-carboxylate 21c,d

To a solution of propan-2-yl 1H-pyrrole-2-carboxylate 20b (3.6 mmol) inanhydrous DMF (15 mL), NaH (7.2 mmol) was added at 0° C. and thereaction mixture was stirred at room temperature for 16 h. Then KI (0.64g, 4.0 mmol), ethyl 4-bromobutyrate or ethyl 5-bromovalerate (7.2 mmol)were added at 0° C. and the reaction mixture was stirred at roomtemperature for 3 h. After cooling, the reaction mixture was poured ontocrushed ice and the aqueous solution was extracted with ethyl acetate(3×50 mL). The organic layers were dried over Na₂SO₄ and the solventremoved under reduced pressure. The crude product was purified bychromatography column (Petroleum ether/AcOEt 9:1).

Propan-2-yl 1-(4-ethoxy-4-oxobutyl)-1H-pyrrole-2-carboxylate (21c). Thiscompound was obtained by reaction of 20b with ethyl 4-bromobutyrate.Colorless oil; yield: 90%; IR: 1729 (CO), 1696 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.13-1.31 (9H, m, 3×CH₃), 1.89-99 (2H, m, CH₂), 2.21(2H, t, J=7.3 Hz, CH₂), 4.03 (2H, q, J=7.1 Hz, CH₂), 4.29 (2H, t, J=7.3Hz, CH₂), 4.95-5.12 (1H, m, CH), 6.08-6.11 (1H, m, Ar), 6.81-6.84 (1H,m, Ar), 7.09-7.15 (1H, m, Ar); ¹³C nmr (DMSO-d₆) (ppm): 14.0 (q), 21.7(2×q), 26.4 (t), 30.5 (t), 47.4 (t), 59.9 (t), 66.6 (d), 107.7 (d),117.8 (d), 121.3 (s), 129.5 (d), 159.7 (s), 172.1 (s). Anal calcd forC₁₄H₂₁NO₄: C, 62.90; H, 7.92; N, 5.24. Found: C, 63.02; H, 8.06; N,5.13.

Propan-2-yl 1-(5-ethoxy-5-oxopentyl)-1H-pyrrole-2-carboxylate (21d).This compound was obtained by reaction of 20b with ethyl5-bromovalerate. Colorless oil; yield: 84%; IR: 1724 (CO), 1695 (CO)cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.12-1.27 (9H, m, 3×CH₃), 1.40-1.51 (2H,m, CH₂), 1.59-1.73 (2H, m, CH₂), 2.28 (2H, t, J=7.2 Hz, CH₂), 4.03 (2H,q, J=7.1 Hz, CH₂), 4.26 (2H, t, J=7.2 Hz, CH₂), 4.97-5.10 (1H, m, CH),6.06-6.09 (1H, m, Ar), 6.80-6.85 (1H, m, Ar), 7.11-7.13 (1H, m, Ar); ¹³Cnmr (DMSO-d₆) (ppm): 14.0 (q), 21.4 (t), 21.7 (2×q), 30.5 (t), 32.9 (t),47.9 (t), 59.6 (t), 66.5 (d), 107.6 (d), 117.7 (d), 121.3 (s), 129.5(d), 159.7 (s), 172.6 (s). Anal calcd for C₁₅H₂₃NO₄: C, 64.03; H, 8.24;N, 4.98. Found: C, 64.19; H, 8.02; N, 5.12.

General Procedure for the Synthesis of4-[2-(substituted)-1H-pyrrol-1-yl]butanoic acid and5-[2-(Substituted)-1H-pyrrol-1-yl]pentanoic acid 22

To a solution of 21 (0.440 g, 1.65 mmol) in EtOH (14 mL) was added asolution of 5% NaOH (1.42 mL, 1.65 mmol). The mixture was stirred atroom temperature or at 70° C. up to completeness (TLC). Then the solventwas removed under reduced pressure and water and crushed ice were added.The solution was acidified with 6 M HCl and the aqueous solution wasextracted with ethyl acetate (3×50 mL). The organic layers were driedover Na₂SO₄ and the solvent removed under reduced pressure. The crudeproduct was purified by chromatography column (DCM/AcOEt 8:2).

4-[2-(Ethoxycarbonyl)-1H-pyrrol-1-yl]butanoic acid (22a). This compoundwas obtained by reaction of ethyl1-(4-ethoxy-4-oxobutyl)-1H-pyrrole-2-carboxylate (21a) after 24 h atroom temperature. Yellow oil; yield: 75%; IR: 3123 (OH), 1716 (CO); 1675(CO)cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.34 (3H, t, J=7.2 Hz, CH₃), 1.90-2.20(2H, m, CH₂), 2.31 (2H, t, J=6.5 Hz, CH₂), 4.21-4.41 (2H, m, 2×CH₂),6.11 (1H, s, Ar), 6.84 (1H, s, Ar), 6.96 (1H, s, Ar), 9.30 (1H, s, OH);¹³C nmr (CDCl₃) (ppm): 14.4 (q), 26.5 (t), 30.7 (t), 47.9 (t), 59.9 (t),108.1 (d), 118.4 (d), 121.8 (s), 128.9 (d), 161.2 (s), 178.2 (s). Analcalcd for C₁₁H₁₅NO₄: C, 58.66; H, 6.71; N, 6.22. Found: C, 58.48; H,6.91; N, 6.10.

5-[2-(Ethoxycarbonyl)-1H-pyrrol-1-yl]pentanoic acid (22b). This compoundwas obtained by reaction of ethyl1-(5-ethoxy-5-oxopentyl)-1H-pyrrole-2-carboxylate (21b) after 72 h atroom temperature. Yellow oil; yield: 65%; IR: 3123 (OH), 1702 (CO); 1681(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.26 (3H, t, J=7.0 Hz, CH₃),1.35-1.49 (2H, m, CH₂), 1.60-1.74 (2H, m, CH₂), 2.21 (2H, t, J=7.3 Hz,CH₂), 4.15-4.31 (4H, m, 2×CH₂), 5.96-6.20 (1H, m, Ar), 6.69-6.93 (1H, m,Ar), 7.12-7.17 (1H, m, Ar), 12.04 (1H, s, OH); ¹³C nmr (DMSO-d₆) (ppm):14.2 (q), 21.4 (t), 30.6 (t), 33.1 (t), 47.9 (t), 59.3 (t), 107.6 (d),117.7 (d), 120.9 (s), 129.6 (d), 160.2 (s), 174.3 (s). Anal calcd forC₁₂H₁₇NO₄: C, 60.24; H, 7.16; N, 5.85. Found: C, 60.37; H, 7.02; N,5.99.

4-{2-[(Propan-2-yloxy)carbonyl]-1H-pyrrol-1-yl}butanoic acid (22c). Thiscompound was obtained by reaction of propan-2-yl1-(4-ethoxy-4-oxobutyl)-1H-pyrrole-2-carboxylate (21c) after 12 h at 70°C. colorless oil; yield: 81%; IR: 3113 (OH), 1706 (CO); 1685 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.26 (6H, d, J=6.2 Hz, 2×CH₃), 1.82-1.92 (2H, m,CH₂), 2.14 (2H, t, J=7.3 Hz, CH₂), 4.28 (2H, t, J=7.3 Hz, CH₂),4.95-5.13 (1H, m, CH), 6.008-6.11 (1H, m, Ar), 6.81-6.84 (1H, m, Ar),7.09-7.11 (1H, m, Ar), 12.15 (1H, s, OH); ¹³C nmr (DMSO-d₆) (ppm): 21.7(2×q), 26.6 (t), 30.5 (t), 47.5 (t), 66.6 (d), 107.7 (d), 117.8 (d),121.3 (s), 129.5 (d), 159.7 (s), 173.8 (s). Anal calcd for C₁₂H₁₇NO₄: C,60.24; H, 7.16; N, 5.85. Found: C, 60.12; H, 7.29; N, 6.05.

5-{2-[(Propan-2-yloxy)carbonyl]-1H-pyrrol-1-yl}pentanoic acid (22d).This compound was obtained by reaction of propan-2-yl1-(5-ethoxy-5-oxopentyl)-1H-pyrrole-2-carboxylate (21d) after 24 h at70° C. Colorless oil; yield: 74%, IR: 3131 (OH), 1704 (CO), 1696 (CO)cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.27 (6H, d, J=6.4 Hz, 2×CH₃), 1.59-1.67(2H, m, CH₂), 1.71-1.76 (2H, m, CH₂), 2.21 (2H, t, J=7.4 Hz, CH₂), 4.26(2H, t, J=7.4 Hz, CH₂), 5.01-5.10 (1H, m, CH), 6.06-6.12 (1H, m, Ar),6.80-6.85 (1H, m, Ar), 7.12-7.16 (1H, m, Ar), 12.05 (1H, s, OH); ¹³C nmr(DMSO-d₆) (ppm): 21.4 (t), 21.7 (2×q), 30.7 (t), 33.1 (t), 47.9 (t),59.6 (t), 66.5 (d), 107.6 (d), 117.7 (d), 121.3 (s), 129.5 (d), 159.8(s), 174.2 (s). Anal calcd for C₁₃H₁₉NO₄: C, 61.64; H, 7.56; N, 5.53.Found: C, 61.52; H, 7.39; N, 5.71.

General Procedure for the Synthesis of ethyl8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylate 23a and ethyl9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate 23b

The suitable acid derivative 22a,b (8.37 mmol) was stirred inpolyphosphoric acid (13 g) at 35° C. for 16 h. The reaction mixture wasquenched with water and crushed ice and the resulting solution wasextracted with ethyl acetate (3×50 mL). The organic layer were driedover Na₂SO₄, and the solvent removed under reduced pressure. The crudeproduct was purified by chromatography column (DCM).

Ethyl 8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylate (23a). Thiscompound was obtained by reaction of4-[2-(ethoxycarbonyl)-1H-pyrrol-1-yl]butanoic acid (22a). Yellow oil;yield: 70%; IR: 1704 (CO), 1687 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.37(3H, t, J=6.7 Hz, CH₃), 2.16.2.41 (2H, m, CH₂), 2.61 (2H, t, J=6.6 Hz,CH₂), 4.31 (2H, q, J=6.7 Hz, CH₂), 4.55 (2H, t, J=6.6 Hz, CH₂), 5.32(1H, s, Ar), 6.90 (1H, s, Ar); ¹³C nmr (CDCl₃) (ppm): 14.2 (q), 23.3(t), 36.0 (t), 44.5 (t), 60.5 (t), 112.4 (d), 116.8 (d), 126.0 (s),135.5 (s), 160.6 (s), 188.3 (s). Anal calcd for C₁₁H₁₃NO₃: C, 63.76; H,6.32; N, 6.76. Found: C, 63.89; H, 6.13; N, 6.61.

Ethyl 9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate(23b). This compound was obtained by reaction of5-[2-(ethoxycarbonyl)-1H-pyrrol-1-yl]pentanoic acid (22b). Yellow oil;yield: 65%; IR: 1708 (CO), 1679 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.37(3H, t, J=7.1 Hz, CH₃), 1.82-1.94 (2H, m, CH₂), 2.00-2.13 (2H, m, CH₂),2.77 (2H, t, J=6.0 Hz, CH₂), 4.32 (2H, q, J=7.1 Hz, CH₂), 4.79 (2H, t,J=6.0 Hz, CH₂), 6.85-6.92 (2H, m, Ar); ¹³C nmr (DMSO-d₆) (ppm): 14.3(q), 19.4 (t), 26.1 (t), 39.6 (t), 44.0 (t), 60.7 (t), 114.6 (d), 116.9(d), 139.8 (s), 161.2 (s), 193.8 (s). Anal calcd for C₁₂H₁₅NO₃: C,65.14; H, 6.83; N, 6.33. Found: C, 64.98; H, 6.72; N, 6.57.

General Procedure for the Synthesis of propan-2-yl8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylate 23c and propan-2-yl9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate 23d

To a solution of 22c,d (4.32 g, 18 mmol) in anhydrous DCM (52 mL)trifluoroacetic anhydride (16.6 mL, 217 mmol) was added and the reactionmixture was stirred at room temperature for 24 h. The solvent wasremoved under reduced pressure and water and crushed ice were added. Thesolution was neutralized with a saturated solution of NaHCO₃. Then theaqueous phase was extracted with dichloromethane (3×50 mL). The organiclayers were dried over Na₂SO₄, and the solvent removed under reducedpressure. The crude product was purified by chromatography column(Cyclohexane/AcOEt 8:2).

Propan-2-yl 8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylate (23c). Thiscompound was obtained by reaction of4-{2-[(propan-2-yloxy)carbonyl]-1H-pyrrol-1-yl}butanoic acid (22c). Paleyellow solid; yield 65%; m.p.: 66-67° C.; IR: 1703 (CO), 1669 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.30 (6H, d, J=6.2 Hz, 2×CH₃), 2.15-2.27 (2H, m,CH₂), 2.57 (2H, t, J=6.0 Hz, CH₂), 4.48 (2H, t, J=6.0 Hz, CH₂),5.04-5.17 (1H, m, CH), 6.80-6.88 (2H, m, Ar); ¹³C nmr (DMSO-d₆) (ppm):21.6 (2×q), 22.8 (t), 35.5 (t), 44.4 (t), 67.9 (d), 111.5 (d), 116.3(d), 125.7 (s), 134.3 (s), 159.6 (s), 188.4 (s). Anal calcd forC₁₂H₁₅NO₃: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.27; H, 7.03; N,6.21.

Propan-2-yl9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate (23d).This compound was obtained by reaction of5-{2-[(propan-2-yloxy)carbonyl]-1H-pyrrol-1-yl}pentanoic acid (22d).Yellow oil; yield: 62%, IR: 1703 (CO), 1658 (CO) cm⁻¹; ¹H nmr (DMSO-d₆)(ppm): 1.29 (6H, d, J=6.2 Hz, 2×CH₃), 1.68-1.80 (2H, m, CH₂), 1.88-1.99(2H, m, CH₂), 2.71-2.77 (2H, m, CH₂), 4.72-4.78 (2H, m, CH₂), 5.06-5.16(1H, m, CH), 6.71-6.86 (2H, m, Ar); ¹³C nmr (DMSO-d₆) (ppm): 18.8 (t),21.6 (2×q), 25.5 (t), 39.0 (t), 43.5 (t), 67.8 (d), 113.5 (d), 116.1(d), 126.0 (s), 139.3 (s), 159.8 (s), 193.1 (s). Anal calcd forC₁₃H₁₇NO₃: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.18; H, 7.09; N,6.07.

General Procedure for the Synthesis of3-substituted-7-(dimethylamino)methylene)-8-oxo-5,6,7,8-tetrahydroindolizine24a,c and3-substituted-8-(dimethylamino)methylene)-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine24b,d

To a solution of 23 (0.44 g, 2 mmol) in anhydrous DMF (2.6 mL) was addedDMFDMA (2.64 mL, 20 mmol). The reaction mixture was stirred at reflux upto completeness (TLC). The reaction mixtures was poured onto crushedice. The precipitate was filtered off and dried, in absence the solutionwas extracted with ethyl acetate (3×30 mL). The organic layer was driedover Na₂SO₄ and the solvent was removed under reduced pressure.

Ethyl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylate(24a). This compound was obtained by reaction of ethyl8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylate (23a) after 2 h andused in the next step without further purification.

Ethyl8-(dimethylamino)methylene)-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate(24b). This compound was obtained by reaction of ethyl9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate (23b)after 3 h: yellow solid; yield: 87%, mp: 115-116° C.; IR: 1697 (CO),1641 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.28 (3H, t, J=7.1 Hz, CH₃),1.86-199 (2H, m, CH₂), 2.32 (2H, t, J=6.3 Hz, CH₂), 3.11 (6H, s, 2×CH₃),4.25 (2H, q, J=7.1 Hz, CH₂), 4.51 (2H, t, J=6.3 Hz, CH₂), 6.44 (1H, d,J=4.0 Hz, Ar), 6.82 (1H, d, J=4.0 Hz, Ar), 7.53 (1H, s, CH); ¹³C nmr(DMSO-d₆) (ppm): 14.2 (q), 21.7 (t), 30.6 (t), 42.9 (t), 43.1 (2×q),59.8 (t), 102.4 (s), 110.6 (d), 116.1 (d), 122.3 (s), 142.1 (s), 150.1(d), 160.4 (s), 184.9 (s). Anal calcd for C₁₅H₂₀N₂O₃: C, 65.20; H, 7.30;N, 10.14. Found: C, 65.08; H, 7.56; N, 10.27.

Propan-2-yl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylate(24c). This compound was obtained by reaction of propan-2-yl8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylate (23c) after 3 h: yellowsolid; yield: 56%, mp: 126-127° C.; IR: 1691 (CO), 1603 (CO) cm⁻¹; ¹Hnmr (DMSO-d₆) (ppm): 1.28 (6H, d, J=6.2 Hz, 2×CH₃), 3.04-3.12 (8H, m,CH₂ and 2×CH₃), 4.41 (2H, t, J=6.6 Hz, CH₂), 5.01-5.14 (1H, m, CH), 6.61(1H, d, J=4.1 Hz, Ar), 6.81 (1H, d, J=4.1 Hz, Ar),7.49 (1H, s, CH); ¹³Cnmr (DMSO-d₆) (ppm): 21.7 (2×q), 23.7 (t), 23.8 (t), 43.2 (2×q), 67.3(d), 98.5 (s), 110.1 (d), 116.5 (d), 123.4 (s), 136.6 (s), 149.2 (d),159.9 (s), 176.5 (s). Anal calcd for C₁₅H₂₀N₂O₃: C, 65.20; H, 7.30; N,10.14. Found: C, 65.34; H, 7.19; N, 10.02.

Propan-2-yl8-[(dimethylamino)methylidene]-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate(24d). This compound was obtained by reaction of propan-2-yl9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate (23d)after 2 h and used in the next step without further purification.

General Procedure for the Synthesis of Compounds Type 25

To a solution of the enamiketones 24 (2.76 mmol) in anhydrous ethanol(20 mL) under nitrogen atmosphere phenylsulfonylacetonitrile (0.75 g,4.14 mmol) was added. The reaction mixture was heated under reflux for24 h. The solvent was removed under reduced pressure.

The crude product was recrystallized from diethyl ether.

Ethyl3-(benzenesulfonyl)-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN1). This compound was obtained by reaction of ethyl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylate(24a). Brown solid; yield: 68%; mp: 145-146° C.; IR: 3365 (NH), 1718(CO), 1646 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.29 (3H, t, J=7.1 Hz,CH₃), 3.01 (2H, t, J=7.0 Hz, CH₂), 4.27 (2H, q, J=7.1 Hz, CH₂), 4.54(2H, t, J=7.0 Hz, CH₂), 6.65 (1H, d, J=4.0 Hz, Ar), 7.16 (1H, d, J=4.0Hz, Ar), 7.55-7.73 (3H, m, Ar), 7.96-8.01 (2H, m, Ar), 8.29 (1H, s,H-4), 12.58 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.2 (q), 24.8 (t),42.1 (t), 60.3 (t), 108.4 (s), 110.4 (d), 117.6 (d), 118.7 (s), 120.1(s), 125.5 (s), 128.0 (2×d), 128.8 (2×d), 133.3 (d), 138.9 (d), 140.3(s), 144.1 (s), 157.1 (s), 159.9 (s). Anal calcd for C₂₀H₁₈N₂O₅S: C,60.29; H, 4.55; N, 7.03. Found: C, 60.54; H, 4.41; N, 6.92.

Ethyl3-(benzenesulfonyl)-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN5). This compound was obtained by reaction of ethyl8-(dimethylamino)methylene)-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate(24b). Yellow solid; yield: 51%, mp: 340-341° C.; IR: 3131 (NH), 1703(CO), 1652 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.29 (3H, t, J=7.1 Hz,CH₃), 2.23-2.26 (2H, m, CH₂), 2.32-2.59 (2H, s, CH₂), 4.27 (2H, q, J=7.1Hz, CH₃), 4.38 (2H, t, J=6.1 Hz, CH₂), 6.64 (1H, d, J=4.2 Hz, Ar), 6.94(1H, d, J=4.2 Hz, Ar), 7.57-7.70 (3H, m, Ar), 8.00 (2H, d, J=6.9 Hz,Ar), 8.33 (1H, s, H-4), 12.54 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.7(q), 27.2 (t), 31.8 (t), 44.0 (t), 60.6 (t), 112.7 (d), 117.0 (d), 117.7(s), 125.7 (s), 126.5 (s), 128.7 (2×d), 129.3 (2×d), 133.3 (s), 133.8(d), 140.7 (s), 145.2 (s), 146.0 (d), 157.6 (s), 160.5 (s). Anal calcdfor C₂₁H₂₀N₂O₅S: C, 61.15; H, 4.89; N, 6.79. Found: C, 61.27; H, 5.02;N, 6.58.

Propan-2-yl3-(benzenesulfonyl)-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN9). This compound was obtained by reaction of isopropyl propan-2-yl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylate(24c). white solid; yield: 61%, mp: 332-333° C.; IR: 3125 (NH), 1703(CO), 1652 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.29 (6H, d, J=6.2 Hz,2×CH₃), 3.00 (2H, t, J=6.7 Hz, CH₂), 4.54 (2H, t, J=6.7 Hz, CH₂),5.07-5.13 (1H, m, CH), 6.91 (2H, d, J=4.1 Hz, Ar), 7.14 (1H, d, J=4.1Hz, Ar), 7.56-7.69 (3H, m, Ar), 7.99 (2H, d, J=7.5 Hz, Ar), 8.29 (1H, s,H-4), 12.57 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 22.1 (2×q), 25.3 (t),42.6 (t), 68.3 (d), 107.5 (s), 110.8 (d), 118.0 (d), 123.9 (s), 126.3(s), 128.5 (2×d), 129.2 (2×d), 133.8 (d), 138.7 (d), 140.8 (s), 145.8(s), 149.7 (s), 157.5 (s), 160.0 (s). Anal calcd for C₂₁H₂₀N₂O₅S: C,61.15; H, 4.89; N, 6.79. Found: C, 61.07; H, 4.72; N, 6.88.

Propan-2-yl3-(benzenesulfonyl)-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN13). This compound was obtained by reaction of propan-2-yl8-[(dimethylamino)methylidene]-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate(24d). White solid; yield: 54%, mp: 237-238° C.; IR: 3131 (NH), 1697(CO), 1646 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.30 (6H, d, J=6.1 Hz,2×CH₃), 2.12-2.34 (2H, m, CH₂), 2.42-2.51 (2H, m, CH₂), 4.29-4.43 (2H,m, CH₂), 5.04-5.16 (1H, m, CH), 6.63 (1H, d, J=4.1 Hz, Ar), 6.91 (1H, d,J=4.1 Hz, Ar), 7.57-7.73 (3H, m, Ar), 8.01 (2H, d, J=6.9 Hz, Ar), 8.33(1H, s, H-4), 12.53 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 21.7 (2×q),26.7 (t), 31.3 (t), 43.6 (t), 67.6 (d), 102.8 (s), 112.1 (d), 116.4 (d),121.4 (s), 125.6 (s), 128.2 (2×d), 128.8 (2×d), 133.4 (d), 137.0 (d),140.1 (s), 145.5 (s), 155.7 (s), 157.2 (s), 159.7 (s). Anal calcd forC₂₂H₂₂N₂O₅S: C, 61.96; H, 5.20; N, 6.57. Found: C, 62.15; H, 5.37; N,6.41.

General Procedure for the Synthesis of Compounds of Type 26 and 27

To a solution of the suitable derivatives of type 25 (15 mmol) inanhydrous DMF (20 mL), NaH (0.64 g, 16 mmol) was added at 0° C. and thereaction mixture was stirred at room temperature. After 6 h, iodomethane(16 mmol) was added at 0° C. and the reaction mixture was stirred atroom temperature for 24 h. Then the reaction mixture was poured ontocrushed ice. The precipitate was filtered off and dried, in absence thesolution was extracted with ethyl acetate (3×30 mL). The organic layerwas dried over Na₂SO₄ and the solvent was removed under reducedpressure. The crude product, containing O-methyl (26) and N-methylsubstituted derivatives (27), was purified by chromatography column(DCM/AcOEt 95:5).

Ethyl3-(benzenesulfonyl)-2-methoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN3). This compound was obtained by reaction of QZN1. Light yellowsolid; yield: 25%, mp: 157-158° C.; IR: 1697 (CO) cm⁻¹; ¹H nmr (CDCl₃)(ppm): 1.37 (3H, t, J=7.1 Hz, CH₃), 3.13 (2H, t, J=6.9 Hz, CH₂), 3.96(3H, s, CH₃), 4.32 (2H, q, J=7.1 Hz, CH₂), 4.67 (2H, t, J=6.9 Hz, CH₂),6.88 (1H, d, J=4.1 Hz, Ar), 7.01 (1H, d, J=4.1 Hz, Ar), 7.46-7.64 (3H,m, 3H—Ar), 7.98-8.03 (2H, m, Ar), 8.23 (1H, s, H-4); ¹³C nmr (CDCl₃)(ppm): 14.4 (q), 26.9 (t), 42.2 (t), 54.0 (q), 60.4 (t), 109.5 (d),118.4 (d), 119.2 (s), 121.0 (s), 124.9 (s), 128.5 (2×d), 128.7 (2×d),133.3 (d), 134.61 (s), 138.5 (d), 140.6 (s), 149.2 (s), 159.11 (s),161.1 (s). Anal calcd for C₂₁H₂₀N₂O₅S: C, 61.15; H, 4.89; N, 6.79.Found: C, 61.27; H, 4.65; N, 6.91.

Ethyl3-(benzenesulfonyl)-1-methyl-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN4). This compound was obtained by reaction of QZN1. Yellow solid;yield: 53%, mp: 250-251° C.; IR: 1709 (CO), 1658 (CO) cm⁻¹; ¹H nmr(CDCl₃) (ppm): 1.38 (3H, t, J=7.1 Hz, CH₃), 2.93 (2H, t, J=6.4 Hz, CH₂),3.77 (3H, s, CH₃), 4.35 (2H, q, J=7.1 Hz, CH₂), 4.68 (2H, t, J=6.4 Hz,CH₂), 6.76 (1H, d, J=4.4 Hz, Ar), 7.03 (1H, d, J=4.4 Hz, Ar), 7.47-7.64(3H, m, 3H—Ar), 8.12-8.18 (2H, m, 2H—Ar), 8.27 (1H, s, H-4); ¹³C nmr(CDCl₃) (ppm): 14.4 (q), 27.7 (t), 35.2 (q), 41.8 (t), 60.9 (t), 110.7(s), 113.9 (d), 117.3 (d), 125.4 (s), 125.5 (s), 127.1 (s), 128.6 (2×d),129.0 (2×d), 133.3 (d), 139.9 (s), 141.5 (d), 143.1 (s), 157.8 (s),160.5 (s). Anal calcd for C₂₁H₂₀N₂O₅S: C, 61.15; H, 4.89; N, 6.79.Found: C, 60.98; H, 5.03; N, 6.53.

Ethyl3-(benzenesulfonyl)-2-methoxy-6,7-dihydro-5H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN7). This compound was obtained by reaction of QZN5. White solid;yield: 23%, mp: 157-158° C.; IR: 1697 cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.38(3H, t, J=7.1 Hz, CH₃), 2.31-2.45 (2H, m, CH₂), 2.70 (2H, t, J=7.0 Hz,CH₂), 3.96 (3H, s, CH₃), 4.27-4.45 (4H, m, 2×CH₂), 6.62 (1H, d, J=4.1Hz, Ar), 7.01 (1H, d, J=4.1 Hz, Ar), 7.49-7.65 (3H, m, Ar), 8.01-8.06(2H, m, Ar), 8.27 (1H, s, H-4); ¹³C nmr (CDCl₃) (ppm): 14.4 (q), 28.7(t), 31.5 (t), 43.8 (t), 51.1 (q), 60.3 (t), 111.0 (d), 117.4 (d), 121.6(s), 125.0 (s), 126.5 (s), 128.6 (2×d), 128.7 (2×d), 133.4 (d), 140.0(s), 140.5 (s), 140.6 (d), 153.4 (s), 158.4 (s), 161.1 (s). Anal calcdfor C₂₂H₂₂N₂O₅S: C, 61.96; H, 5.20; N, 6.57. Found: C, 62.08; H, 5.45;N, 6.37.

Ethyl3-(benzenesulfonyl)-1-methyl-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN8). This compound was obtained by reaction of QZN5. Yellow solid;Yield: 45%, mp: 238-239° C.; IR: 1697 (CO), 1658 (CO) cm⁻¹; ¹H nmr(CDCl₃) (ppm): 1.39 (3H, t, J=7.1 Hz, CH₃), 2.05-2.19 (2H, m, CH₂),2.37-2.62 (2H, m, CH₂), 3.60 (3H, s, CH₃), 4.34 (2H, q, J=7.1 Hz, CH₂),5.35-5.45 (2H, m, CH₂), 6.37 (1H, d, J=4.2 Hz, Ar), 7.04 (1H, d, J=4.2Hz, Ar), 7.49-7.65 (3H, m, Ar), 8.11-8.18 (2H, m, Ar), 8.28 (1H, s,H-4); ¹³C nmr (CDCl₃) (ppm): 14.4 (q), 28.3 (t), 31.9 (t), 35.3 (q),43.3 (t), 60.6 (t), 112.6 (d), 116.3 (s), 116.8 (d), 124.4 (s), 127.6(s), 128.6 (2×d), 129.1 (2×d), 130.6 (s), 133.4 (d), 139.7 (s), 143.3(d), 145.8 (s), 157.6 (s), 160.7 (s). Anal calcd for C₂₂H₂₂N₂O₅S: C,61.96; H, 5.20; N, 6.57. Found: C, 61.83; H, 5.13; N, 6.65.

Propan-2-yl3-(benzenesulfonyl)-2-methoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN11). This compound was obtained by reaction of QZN9. Yellow solid;yield: 24%, mp: 168-169° C.; IR: 1692 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm):1.35 (6H, d, J=6.2 Hz, 2×CH₃), 3.31 (2H, t, J=6.9 Hz, CH₂), 3.97 (3H, s,CH₃), 4.67 (2H, t, J=6.9 Hz, CH₂), 5.13-5.26 (1H, m, CH), 6.88 (1H, d,J=4.1 Hz Ar), 6.99 (1H, d, J=4.1 Hz, Ar), 7.47-7.63 (3H, m, Ar), 8.03(2H, d, J=6.6 Hz Ar), 8.22 (1H, s, H-4); ¹³C nmr (CDCl₃) (ppm): 22.0(2×q), 26.9 (t), 42.2 (t), 54.0 (q), 67.9 (d), 109.4 (d), 118.2 (d),119.1. (s), 120.9 (s), 125.4 (s), 128.5 (2×d), 128.7 (2×d), 133.3 (d),134.5 (s), 138.5 (d), 140.7 (s), 149.2 (s), 159.1 (s), 160.7 (s). Analcalcd for C₂₂H₂₂N₂O₅S: C, 61.96; H, 5.20; N, 6.57. Found: C, 61.76; H,5.04; N, 6.75.

Propan-2-yl3-(benzenesulfonyl)-1-methyl-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN12). This compound was obtained by reaction of QZN9. Yellow solid;yield: 45%, mp: 207-208° C.; IR: 1703 (CO), 1658 (CO) cm⁻¹; ¹H nmr(CDCl₃) (ppm): 1.36 (6H, d, J=6.2 Hz, 2×CH₃), 2.92 (2H, t, J=7.2 Hz,CH₂), 3.77 (3H, s, CH₃), 4.68 (2H, t, J=7.2 Hz, CH₂), 5.18-5.24 (1H, m,CH), 6.75 (1H, d, J=4.4 Hz, Ar), 7.01 (1H, d, J=4.4 Hz, Ar), 7.47-7.63(3H, m, Ar), 8.11-8.17 (2H, m, Ar), 8.27 (1H, s, H-4); ¹³C nmr (CDCl₃)(ppm): 21.9 (2×q), 27.7 (t), 35.1 (q), 41.8 (t), 68.5 (d), 110.7 (s),113.8 (d), 117.2 (d), 125.4 (s), 125.8 (s), 126.9 (s), 128.6 (2×d),129.1 (2×d), 133.3 (d), 139.9 (s), 141.5 (d), 143.2 (s), 157.8 (s),160.1 (s). Anal calcd for C₂₂H₂₂N₂O₅S: C, 61.96; H, 5.20; N, 6.57.Found: C, 62.11; H, 5.34; N, 6.39.

Propan-2-yl3-(benzenesulfonyl)-2-methoxy-6,7-dihydro-5H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN15). This compound was obtained by reaction of QZN13. White solid;yield: 28%, mp: 211-212° C.; IR: 1696 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm):1.35 (6H, d, J=6.2 Hz, 2×CH₃), 2.35-2.44 (2H, m, CH₂), 2.64-2.73 (2H, m,CH₂), 3.95 (3H, s, CH₃), 4.41 (2H, t, J=6.5 Hz, CH₂), 5.16 (1H, m, CH),6.62 (1H, d, J=4.1 Hz, Ar), 7.00 (1H, d, J=4.1 Hz, Ar), 7.49-7.65 (3H,m, Ar), 8.0 (2H, d, J=6.8 Hz, Ar), 8.27 (1H, s, H-4); ¹³C nmr (CDCl₃)(ppm): 22.1 (2×q), 28.7 (t), 31.5 (t), 43.7 (t), 51.1 (q), 67.7 (d),109.9 (d), 117.3 (d), 121.6 (s), 125.5 (s), 126.5 (s), 128.6 (2×d),128.7 (2×d), 133.4 (d), 139.9 (s), 140.5 (d), 153.4 (s), 158.4 (s),159.8 (s), 160.7 (s). Anal calcd for C₂₃H₂₄N₂O₅S: C, 62.71; H, 5.49; N,6.36. Found: C, 62.89; H, 5.64; N, 6.18.

Propan-2-yl3-(benzenesulfonyl)-1-methyl-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN16). This compound was obtained by reaction of QZN13. Yellow solid;Yield: 41%, mp: 253-254° C.; IR: 1697 (CO), 1658 (CO) cm⁻¹; ¹H nmr(CDCl₃) (ppm): 1.37 (6H, d, J=6.2 Hz, 2×CH₃), 2.08-2.61 (4H, m, 2×CH₂),3.60 (3H, s, CH₃), 5.15-5.44 (3H, m, CH₂ and CH), 6.35 (1H, d, J=4.1 Hz,Ar), 7.02 (1H, d, J=4.1 Hz, Ar), 7.54-7.62 (3H, m, Ar), 8.14-8.19 (2H,m, Ar), 8.29 (1H, s, H-4); ¹³C nmr (CDCl₃) (ppm): 22.0 (2×q), 28.4 (t),31.8 (t), 35.3 (q), 43.3 (t), 68.2 (d), 112.5 (d), 116.3 (s), 117.8 (d),124.9 (s), 127.7 (s), 128.6 (2×d), 129.2 (2×d), 130.5 (s), 133.4 (d),139.7 (s), 143.3 (d), 145.9 (s), 157.6 (s), 160.2 (s). Anal calcd forC₂₃H₂₄N₂O₅S: C, 62.71; H, 5.49; N, 6.36. Found: C, 62.59; H, 5.36; N,6.49.

General Procedure for the Synthesis of Compounds of Type 28

To a solution of suitable tricyclic compounds of type 25 (0.22 mmol) inanhydrous DCM (20 ml), Br₂ (0.44 mmol, 0.02 mL) was added at 0° C. andthe reaction mixture was stirred at room temperature for 24 h. Then thereaction mixture was evaporated under reduced pressure. The crudeproduct was recrystallized from diethyl ether.

Ethyl3-(benzenesulfonyl)-9-bromo-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN2). This compound was obtained by reaction of QZN1. Yellow solid;yield: 63%; mp: 196-197° C.; IR: 3342 (NH), 1700 (CO), 1669 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.37 (3H, t, J=7.1 Hz, CH₃), 2.99 (2H, t, J=7.0Hz, CH₂), 4.33 (2H, q, J=7.1 Hz, CH₂), 4.67 (2H, t, J=7.0 Hz, CH₂), 7.03(1H, s, Ar), 7.49-7.65 (3H, m, Ar), 8.09-8.17 (2H, m, Ar), 8.31 (1H, s,H-4), 10.02 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.3 (q), 23.8 (t),42.8 (t), 61.3 (t), 97.5 (s), 108.2 (s), 120.8 (d), 122.3 (s), 126.2(s), 127.9 (s), 128.7 (2×d), 129.0 (2×d), 133.6 (d), 138.8 (s), 139.6(s), 143.8 (d), 156.0 (s), 159.6 (s). Anal calcd for C₂₀H₁₇BrN₂O₅S: C,50.32; H, 3.59; N, 5.87. Found: C, 50.54; H, 3.70; N, 5.69.

Ethyl3-(benzenesulfonyl)-10-bromo-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN6). This compound was obtained by reaction of QZN5. White solid;yield: 90%, mp: 172-173° C.; IR: 3399 (NH), 1705 (CO), 1652 (CO) cm⁻¹;¹H nmr (CDCl₃) (ppm): 1.33 (3H, t, J=7.1 Hz, CH₃), 2.18-2.21 (2H, m,CH₂), 2.38-2.46 (2H, m, CH₂), 4.21-4.38 (4H, m, 2×CH₂), 7.05 (1H, s,Ar), 7.58-7.75 (3H, m, Ar), 8.02 (2H, d, J=6.9 Hz, Ar), 8.37 (1H, s,H-4), 12.48 (1H, s, NH); ¹³C nmr (CDCl₃) (ppm): 14.0 (q), 26.0 (t), 31.4(t), 46.7 (t), 61.1 (t), 98.0 (s), 106.7 (s), 119.2 (d), 123.0 (s),124.6 (s), 128.3 (2×d), 128.8 (2×d), 134.0 (d), 140.3 (s), 140.4 (s),147.9 (d), 157.3 (s), 159.1 (s), 159.7 (s). Anal calcd forC₂₁H₁₉BrN₂O₅S: C, 51.33; H, 3.90; N, 5.70. Found: C, 51.45; H, 4.05; N,5.59.

Propan-2-yl3-(benzenesulfonyl)-9-bromo-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN10). This compound was obtained by reaction of QZN9. White solid;yield: 69%, mp: 174-175° C.; IR: 3336 (NH), 1705 (CO), 1669 (CO) cm⁻¹;¹H nmr (CDCl₃) (ppm): 1.40 (6H, d, J=6.1 Hz, 2×CH₃), 2.94-3.18 (2H, m,CH₂), 4.59-4.83 (2H, m, CH₂), 5.15-5.36 (1H, m, CH), 7.02 (1H, s, Ar),7.45-7.69 (3H, m, Ar), 8.11-8.22 (2H, m, Ar), 8.37 (1H, s, H-4), 9.25(1H, s, NH); ¹³C nmr (CDCl₃) (ppm): 22.1 (2×q), 26.3 (t), 43.7 (t), 69.2(d), 98.0 (s), 102.7 (s), 109.3 (s), 120.9 (d), 122.4 (s), 124.9 (s),126.8 (s), 129.1 (2×d), 129.5 (2×d), 133.7 (d), 144.6 (d), 156.3 (s),158.7 (s), 159.1 (s). Anal calcd for C₂₁H₁₉BrN₂O₅S: C, 51.33; H, 3.90;N, 5.70. Found: C, 51.23; H, 4.11; N, 5.53.

Propan-2-yl3-(benzenesulfonyl)-10-bromo-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN14). This compound was obtained by reaction of QZN13. White solid;yield: 84%, mp: 167-168° C.; IR: 3422 (NH), 1702 (CO), 1646 (CO) cm⁻¹;¹H nmr (DMSO-d₆) (ppm): 1.28-1.35 (6H, m, 2×CH₃), 2.18-2.41 (2H, m,CH₂), 2.44 (2H, s, CH₂), 4.14-4.40 (2H, m, CH₂), 5.03-5.15 (1H, m, CH),7.00 (1H, s, H—Ar), 7.58-7.72 (3H, m, 3×H-Ar), 8.01 (2H, d, 2H—Ar), 8.37(1H, s, 1H—Ar), 12.11-12.81 (1H, m, NH); ¹³C nmr (DMSO-d₆) (ppm): 22.6(2×q), 25.4 (t), 28.8 (t), 48.6 (t), 69.9 (d), 98.6 (s), 121.2 (d),124.4 (s), 125.3 (s), 129.1 (2×d), 129.5 (2×d), 133.8 (d), 134.0 (s),135.5 (s), 138.0 (s), 139.9 (s), 145.1 (d), 157.1 (s), 161.5 (s). Analcalcd for C₂₂H₂₁BrN₂O₅S: C, 52.28; H, 4.19; N, 5.54. Found: C, 52.14; H,4.04; N, 5.77.

General Procedure for the Synthesis of Compound of Type 29 (R^(a)=H)

To a suspension of MeONa (0.81 g, 15 mmol) in anhydrous ethanol (20 mL),guanidine nitrate (0.92 g, 7.5 mmol) and a solution of the suitableenaminoketons of type 24 (2 mmol) in anhydrous ethanol (20 mL) wereadded. The reaction mixture was heated at reflux up to completeness(TLC). Then the reaction mixture was poured onto crushed ice and theprecipitate was filtered off, dried and purified by chromatography(DCM/AcOEt 9:1).

Ethyl 2-amino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate (QZQ1)This compound was obtained by reaction of ethyl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylateafter 7 h. White solid; yield: 62%; mp: 222-223° C.; IR: 3270-3160(NH₂), 1663 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.29 (3H, t, J=7.1 Hz,CH₃), 2.91 (2H, t, J=6.8 Hz, CH₂), 4.26 (2H, q, J=7.1 Hz, CH₃), 4.54(2H, t, J=6.8 Hz, CH₂), 6.53 (2H, s, NH₂), 6.76 (1H, d, J=4.1 Hz, Ar),6.94 (1H, d, J=4.1 Hz, Ar), 8.17 (1H, s, H-4); ¹³C nmr (DMSO-d₆) (ppm):14.2 (q), 23.4 (t), 42.3 (t), 59.9 (t), 108.0 (d), 112.1 (s), 117.5 (d),124.0 (s), 134.1 (s), 152.9 (s), 156.7 (d), 160.2 (s), 162.9 (s). Analcalcd for C₁₃H₁₄N₄O₂: C, 60.45; H, 5.46; N, 21.69. Found: C, 60.58; H,5.39; N, 21.80.

Ethyl2-amino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ5). This compound was obtained by reaction of ethyl8-(dimethylamino)methylene)-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylateafter 3 h. White solid; yield: 41%; mp: 180-181° C.; 3411-3320 (NH₂),1696 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.30 (3H, t, J=7.1 Hz, CH₃),2.14-2.20 (2H, m, CH₂), 2.42 (2H, t, J=6.3 Hz, CH₂), 4.20-4.36 (4H, m,2×CH₂), 6.54 (1H, d, J=4.0 Hz, Ar), 6.59 (2H, s, NH₂) 6.93 (1H, d, J=4.0Hz, Ar), 8.18 (1H, s, H-4); ¹³C nmr (DMSO-d₆) (ppm): 14.2 (q), 24.8 (t),30.5 (t), 43.6 (t), 59.8 (t), 109.7 (d), 116.8 (d), 118.3 (s), 123.8(s), 139.8 (s), 157.6 (s), 158.5 (d), 160.2 (s), 162.9 (s). Anal calcdfor C₁₄H₁₆N₄O₂: C, 61.75; H, 5.92; N, 20.58. Found: C, 61.62; H, 5.77;N, 20.72.

Propan-2-yl 2-amino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ7). This compound was obtained by reaction of propan-2-yl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylateafter 1 h. White solid; yield: 71%; mp: 211-212° C.; IR: 3414-3332(NH₂), 1695 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.35 (6H, d, J=6.2 Hz,2×CH₃), 2.96 (2H, t, J=6.8 Hz, CH₂), 5.14-4.65 (2H, t, J=6.8 Hz, CH₂),5.12-5.25 (3H, m, CH and NH₂), 6.91-7.03 (2H, m, Ar), 8.15 (1H, s, H-4);¹³C nmr (CDCl₃) (ppm): 22.1 (2×q), 24.4 (t), 42.5 (t), 67.9 (d), 109.3(d), 113.6 (s), 118.1 (d), 125.6 (s), 133.8 (s), 154.4 (s), 156.1 (d),160.7 (s), 162.5 (s). Anal calcd for C₁₄H₁₆N₄O₂: C, 61.75; H, 5.92; N,20.58. Found: C, 61.89; H, 6.11; N, 20.33.

Propan-2-yl2-amino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ21). This compound was obtained by reaction of propan-2-yl8-[(dimethylamino)methylidene]-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylateafter 1 h. White solid; yield: 86%; mp: 176-177° C.; IR: 3514-3411(NH₂), 1692 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.30 (6H, d, J=6.0 Hz,2×CH₃), 2.09-2.24 (2H, m, CH₂), 2.41-2.51 (2H, m, CH₂), 4.24-4.32 (2H,m, CH₂), 5.06-5.12 (1H, m, CH), 6.51-6.61 (2H, m, Ar and NH₂), 6.92 (1H,s, Ar), 8.18 (1H, s, H-4); ¹³C nmr (DMSO-d₆) (ppm): 22.16 (2×q), 27.9(t), 31.1 (t), 47.3 (t), 68.9 (d), 108.7 (d), 117.7 (s), 126.9 (d),121.1 (s), 128.5 (s), 148.2 (s), 154.6 (d), 161.1 (s), 162.2 (s). Analcalcd for C₁₅H₁₈N₄O₂: C, 62.92; H, 6.34; N, 19.57. Found: C, 63.09; H,6.52; N, 19.38.

General Procedure for the Synthesis of Compounds of Type 29

A solution of the suitable enaminoketons 24 (1.5 mmol) andphenylguanidine (R^(a)=Ph), cyclohexylguanidine (R^(a)=cyclohexyl) orcyclopentylguanidine (R^(a)=cyclopentyl) (4.5 mmol) in anhydrous DMF (8mL) was heated at 100° C. up to completeness (TLC). Then the reactionmixture was poured onto crushed ice and the precipitate was filteredoff, dried and purified by chromatography (DCM).

Ethyl 2-anilino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ2). This compound was obtained by reaction of ethyl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylatewith phenylguanidine after 1 h. Yellow solid; Yield: 55%; mp: 177-178°C.; IR: 3417 (NH), 1698 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.31 (3H, t,J=7.1 Hz, CH₃), 3.02 (2H, t, J=6.8 Hz, CH₂), 4.28 (2H, q, J=7.1 Hz,CH₂), 4.60 (2H, t, J=6.8 Hz, CH₂), 6.89-7.01 (2H, m, Ar), 77.24-7.33(3H, m, Ar), 7.83 (2H, d, J=7.7 Hz, Ar), 8.41 (1H, s, H-4), 9.58 (1H, s,NH); ¹³C nmr (DMSO-d₆) (ppm): 14.2 (q), 23.4 (t), 42.2 (t), 60.0 (t),108.6 (d), 114.3 (s), 117.7 (d), 118.4 (2×d), 121.0 (d), 128.4 (2×d),133.8 (s), 140.8 (s), 152.7 (s), 156.5 (d), 159.2 (s), 159.8 (s), 160.1(s). Anal calcd for C₁₉H₁₈N₄O₂: C, 68.25; H, 5.43; N, 16.76. Found: C,68.13; H, 5.57; N, 16.89.

Ethyl2-(cyclohexylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ3). This compound was obtained by reaction of ethyl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylatewith cyclohexylguanidine after 6 h. White solid; yield: 52%; mp:130-131° C.; IR: 3433 (NH), 1697 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):1.09-1.33 (13H, m, CH₃ and 5×CH₂), 2.92 (2H, t, J=6.6 Hz, CH₂),3.70-3.73 (1H, m, CH), 4.25 (2, q, J=7.1 Hz, CH₂), 4.54 (2H, t, J=6.6Hz, CH₂), 6.76 (1H, d, J=4.1 Hz, Ar), 6.89-6.96 (2H, m, Ar and NH), 8.19(1H, s, H-4); ¹³C nmr (DMSO-d₆) (ppm): 14.2 (q), 23.4 (t), 24.8 (2×t),25.4 (t), 32.4 (2×t), 42.4 (t), 49.3 (d), 59.9 (t), 108.0 (d), 111.6(s), 117.5 (d), 124.0 (s), 134.3 (s), 152.8 (s), 156.4 (d), 160.2 (s),161.1 (s). Anal calcd for C₁₉H₂₄N₄O₂: C, 67.04; H, 7.11; N, 16.46.Found: C, 67.29; H, 6.98; N, 16.32.

Ethyl2-anilino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ6). This compound was obtained by reaction of ethyl8-(dimethylamino)methylene)-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylatewith phenylguanidine after 5 h. White solid; yield: 56%; mp: 134-135°C.; IR: 3443 (NH), 1697 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.31 (3H, t,J=7.1 Hz, CH₃), 2.20-2.26 (2H, m, CH₂), 2.50-2.57 (2H, m, CH₂),4.22-4.42 (4H, m, 2×CH₂), 6.71 (1H, d, J=4.1 Hz, Ar), 6.89-7.00 (2H, m,Ar), 7.28 (2H, t, J=8.3 Hz, Ar), 7.81 (2H, d, J=7.6 Hz, Ar), 8.43 (1H,s, H-4), 9.67 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.2 (q), 25.1 (t),30.6 (t), 43.8 (t), 59.9 (t), 110.4 (d), 116.3 (d), 118.5 (2×d), 120.6(s), 121.0 (d), 124.4 (s), 128.4 (2×d), 139.4 (s), 140.7 (s), 157.3 (s),158.4 (d), 159.1 (s), 160.2 (s). Anal calcd for C₂₀H₂₀N₄O₂: C, 68.95; H,5.79; N, 16.08. Found: C, 69.12; H, 5.64; N, 15.96.

Ethyl2-(cyclohexylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ7). This compound was obtained by reaction of ethyl8-(dimethylamino)methylene)-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylatewith cyclohexylguanidine after 2 h. Yellow solid; yield: 61%; mp: 98-99°C.; IR: 3422 (NH), 1693 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.09-1.90(13H, m, CH₃ and 5×CH₂), 2.10-2.24 (2H, m, CH₂), 2.41 (2H, t, J=6.5 Hz,CH₂), 3.72-3.82 (1H, m, CH), 4.20-4.37 (2H, m, 2×CH₂), 6.39 (1H, d,J=4.0 Hz, Ar), 6.92-7.03 (2H, m, Ar and NH), 8.19 (1H, d, H-4); ¹³C nmr(DMSO-d₆) (ppm): 14.2 (q), 24.8 (3×t), 25.4 (t), 30.4 (t), 32.4 (2×t),43.6 (t), 49.2 (d), 59.8 (t), 109.5 (d), 116.8 (d), 123.8 (s), 124.0(s), 139.9 (s), 141.6 (s), 158.3 (d), 160.2 (s), 161.0 (s). Anal calcdfor C₂₀H₂₆N₄O₂: C, 67.77; H, 7.39; N, 15.81. Found: C, 67.64; H, 7.27;N, 15.99.

Propan-2-yl 2-anilino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ18). This compound was obtained by reaction of propan-2-yl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylatewith phenylguanidine after 3 h. White solid; yield: 79%; mp: 184-185°C.; IR: 3422 (NH), 1695 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.30 (6H, d,J=6.2 Hz, 2×CH₃), 3.01 (2H, t, J=6.8 Hz, CH₂), 4.68 (2H, t, J=6.8 Hz,CH₂), 5.14-5.26 (1H, m, CH), 6.98-7.07 (3H, m, Ar and NH), 7.21-7.39(3H, m, Ar), 7.68 (1H, d, J=7.7 Hz, Ar), 8.26 (1H, s, H-4); ¹³C nmr(CDCl₃) (ppm): 22.1 (2×q), 24.4 (t), 42.5 (t), 67.9 (d), 109.3 (d),114.4 (s), 118.1 (d), 118.9 (2×d), 122.2 (d), 125.6 (s), 128.9 (2×d),134.0 (s), 139.8 (s), 154.0 (s), 156.1 (d), 159.5 (s), 160.1 (s). Analcalcd for C₂₀H₂₀N₄O₂: C, 68.95; H, 5.79; N, 16.08. Found: C, 68.79; H,5.91; N, 16.21.

Propan-2-yl2-(cyclohexylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ19). This compound was obtained by reaction of propan-2-yl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylatewith cyclohexylguanidine after 2 h. Yellow solid; yield: 86%; mp:123-124° C.; IR: 3399 (NH), 1694 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm):1.27-1.86 (16H, m, 2×CH₃ and 5×CH₂), 2.64-2.73 (2H, m, CH₂), 3.12-3.22(1H, m, CH), 4.38-4.44 (2H, m, CH₂), 5.01-5.13 (1H, m, CH), 6.59 (1H, d,J=4.1 Hz, Ar), 6.82 (1H, d, J=4.1 Hz, Ar), 7.27 (1H, s, H-4),10.04-10.14 (1H, m, NH); ¹³C nmr (DMSO-d₆) (ppm): 21.7 (2×q), 24.0(2×t), 24.7 (t), 26.4 (t), 33.4 (2×t), 33.7 (t), 55.8 (d), 67.3 (d),96.4 (s), 109.8 (d), 116.5 (d), 123.5 (s), 136.8 (s), 136.9 (s), 151.4(d), 159.9 (s). Anal calcd for C₂₀H₂₆N₄O₂: C, 67.77; H, 7.39; N, 15.81.Found: C, 67.89; H, 7.51; N, 15.69.

Propan-2-yl2-anilino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ22). This compound was obtained by reaction of propan-2-yl8-[(dimethylamino)methylidene]-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylatewith phenylguanidine after 2 h. White solid; yield: 80%; mp: 101-102°C.; IR: 3421 (NH), 1691 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.36 (6H, d,J=6.1 Hz, 2×CH₃), 2.30-2.39 (2H, m, CH₂), 2.59 (2H, t, J=7.0 Hz, CH₂),4.46 (2H, t, J=7.0 Hz, CH₂), 5.14-5.29 (1H, m, CH), 6.75 (1H, d, J=3.6Hz, Ar), 6.69-7.06 (2H, m, Ar and NH), 7.26-7.37 (3H, m, Ar), 7.66 (1H,d, J=7.8 Hz, Ar),8.28 (1H, s, H-4); ¹³C nmr (CDCl₃) (ppm): 22.3 (2×q),27.8 (t), 31.0 (t), 46.9 (t), 68.9 (d), 108.7 (d), 121.0 (s), 122.0(2×d), 123.9 (d), 122.1 (s), 126.9 (d), 128.5 (s), 129.9 (2×d), 139.9(s), 147.7 (s), 156.1 (d), 159.7 (s), 161.4 (s). Anal calcd forC₂₁H₂₂N₄O₂: C, 69.59; H, 6.12; N, 15.46. Found: C, 69.71; H, 6.34; N,15.32.

Propan-2-yl2-(cyclohexylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ23). This compound was obtained by reaction of propan-2-yl8-[(dimethylamino)methylidene]-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylatewith cyclohexylguanidine after 4 h. White solid; yield: 98%; mp:108-109° C.; IR: 3381 (NH), 1685 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm):1.03-1.35 (10H, m, 2×CH₃ and 2×CH₂), 1.59-1.80 (4H, m, 2×CH₂), 1.93-2.10(4H, m, 2×CH₂), 2.15-2.21 (2H, m, CH₂), 3.10-3.16 (1H, m, CH), 4.53 (2H,t, J=6.3 Hz, CH₂), 5.10-5.23 (1H, s, CH), 6.56 (1H, d, J=4.1 Hz, Ar),6.86-6.92 (2H, m, Ar), 10.28-10.37 (1H, m, NH); ¹³C nmr (CDCl₃) (ppm):22.0 (2×q), 24.5 (2×t), 25.2 (t), 26.9 (t), 31.1 (t), 34.1 (2×t), 43.5(t), 57.4 (d), 67.5 (d), 102.4 (2×s), 110.2 (d), 116.7 (d), 123.9 (s),142.6 (s), 152.3 (d), 160.9 (s), 185.1 (s). Anal calcd for C₂₁H₂₈N₄O₂:C, 68.45; H, 7.66; N, 15.21. Found: C, 68.32; H, 7.79; N, 15.08.

Ethyl2-(cyclopentylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ14). This compound was obtained by reaction of ethyl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylatewith cyclopentylguanidine after 2 h. Pale yellow solid; yield: 52%; mp:95-96° C.; IR: 3405 (NH), 1699 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.28(3H, t, J=7.1 Hz, CH₃), 1.48-1.67 (6H, m, 3×CH₂), 1.87-1.99 (2H, m,CH₂), 2.64-274 (2H, m, CH₂), 3.72-3.85 (1H, m, CH), 4.24 (2H, q, J=7.1Hz, CH₂), 4.33-4.51 (2H, m, CH₂), 6.59-6.62 (1H, m, Ar), 6.81-6.90 (1H,m, Ar), 7.31-7.35 (1H, m, Ar), 10.01-10.11 (1H, m, NH); ¹³C nmr(DMSO-d₆) (ppm): 14.2 (q), 23.0 (2×t), 26.4 (t), 33.5 (2×t), 43.9 (t),59.1 (d), 59.9 (t), 96.5 (s), 109.4 (d), 116.8 (d), 123.2 (s), 136.8(s), 137.0 (s), 151.9 (d), 160.3 (s), 176.7 (s). Anal calcd forC₁₈H₂₂N₄O₂: C, 66.24; H, 6.79; N, 17.17. Found: C, 66.12; H, 6.91; N,17.08.

Ethyl2-(cyclopentylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ15). This compound was obtained by reaction of ethyl8-(dimethylamino)methylene)-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylatewith cyclopentylguanidine after 3 h. Yellow solid; yield: 61%; mp:98-99° C.; IR: 3405 (NH), 1696 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.31(3H, t, J=7.1 Hz, CH₃), 1.49-1.68 (6H, m, 3×CH₂), 1.90-2.24 (4H, m,2×CH₂), 3.72-3.82 (1H, m, CH), 4.23 (2H, q, J=7.1 Hz, CH₂), 4.38-4.47(2H, m, CH₂), 6.39-6.41 (1H, m, Ar), 6.80.6.83 (1H, m, Ar), 7.454-7.61(1H, m, Ar), 10.20-10.30 (1H, m, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.2 (q),23.0 (2×t), 25.8 (t), 30.4 (t), 33.5 (2×t), 43.1 (t), 59.2 (d), 59.8(t), 101.4 (s), 109.5 (d), 116.1 (s), 116.2 (d), 122.4 (s), 142.5 (s),147.6 (s), 153.6 (d), 160.3 (s). Anal calcd for C₁₉H₂₄N₄O₂: C, 67.04; H,7.11; N, 16.46. Found: C, 67.22; H, 6.96; N, 16.31.

Propan-2-yl2-(cyclopentylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ20). This compound was obtained by reaction of propan-2-yl7-[(dimethylamino)methylidene]-8-oxo-5,6,7,8-tetrahydroindolizine-3-carboxylatewith cyclopentylguanidine after 3 h. White solid; yield: 73%; mp:124-125° C.; IR: 3406 (NH), 1692 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.33(6H, d, J=6.3 Hz, 2×CH₃), 1.64-1.99 (8H, m, 4×CH₂), 2.70 (2H, t, J=6.4Hz, CH₂), 3.64-3.73 (1H, m, CH), 4.52 (2H, t, J=6.4 Hz, CH₂), 5.11-5.23(1H, m, J=6.2 Hz, CH), 6.79-6.93 (3H, m, Ar), 10.09-10.18 (1H, m, NH);¹³C nmr (CDCl₃) (ppm): 22.0 (2×q), 23.5 (2×t), 27.4 (t), 34.1 (2×t),44.2 (t), 60.2 (d), 67.7 (d), 97.1 (s), 110.1 (d), 117.4 (d), 124.5 (s),132.5 (s), 137.0 (s), 151.1 (d), 160.9 (s), 178.2 (s). Anal calcd forC₁₉H₂₄N₄O₂: C, 67.04; H, 7.11; N, 16.46. Found: C, 66.91; H, 7.23; N,16.58.

Propan-2-yl2-(cyclopentylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ24). This compound was obtained by reaction of propan-2-yl8-[(dimethylamino)methylidene]-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylatewith cyclopentylguanidine after 2 h. Brown solid; yield: 82%; mp:140-141° C.; IR: 3416 (NH), 1690 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.34(6H, d, J=6.2 Hz, 2×CH₃), 1.60-1.78 (6H, m, 3×CH₂), 1.82-2.22 (6H, m,3×CH₂), 3.65-3.77 (1H, m, CH), 4.53 (2H, t, J=6.2 Hz, CH₂), 5.10-5.23(1H, m, CH), 6.55 (1H, d, J=4.0 Hz, Ar), 6.84-6.95 (2H, m, Ar),10.32-10.36 (1H, m, NH); ¹³C nmr (CDCl₃) (ppm): 22.0 (2×q), 23.5 (2×t),26.8 (t), 31.0 (t), 34.1 (2×t), 43.5 (t), 60.2 (d), 67.5 (d), 102.5(2×s), 110.2 (d), 116.7 (d), 124.0 (s), 142.6 (s), 152.9 (d), 160.9 (s),185.1 (s). Anal calcd for C₂₀H₂₆N₄O₂: C, 67.77; H, 7.39; N, 15.81.Found: C, 67.90; H, 7.54; N, 15.63.

General Procedure for the Synthesis of Compounds of Type 30

To a solution of compounds of type 29 (R^(a)=H) (0.15 g, 0.52 mmol) inanhydrous dioxane (20 mL) acetyl chloride (0.057 mL, 0.78 mmol) andtriethylamine (0.08 mL, 0.57 mmol) were added and the reaction mixturewas stirred at reflux up to completeness (TLC). Then the reactionmixture was poured onto crushed ice and the precipitate was filteredoff, dried and purified by chromatography (DCM).

Ethyl 2-acetamido-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ4). This compound was obtained by reaction of QZQ1 after 4 h. Whitesolid; yield: 77%, mp: 249-250° C.; IR: 3403 (NH), 1663 (CO), 1651 (CO)cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.31 (3H, t, J=7.1 Hz, CH₃), 2.22 (3H, s,CH₃), 3.08 (2H, t, J=6.8 Hz, CH₂), 4.28 (2H, q, J=7.1 Hz, CH₂), 4.62(2H, t, J=6.8 Hz, CH₂), 6.88 (1H, d, J=4.1 Hz, Ar), 6.99 (1H, d, J=4.1Hz, Ar), 8.54 (1H, s, H-4), 10.46 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):14.2 (q), 23.5 (t), 24.6 (q), 41.9 (t), 60.1 (t), 109.1 (d), 117.7 (d),118.5 (s), 124.8 (s), 133.2 (s), 153.1 (s), 156.6 (d), 156.8 (s), 160.1(s), 169.2 (s). Anal calcd for C₁₅H₁₆N₄O₃: C, 59.99; H, 5.37; N, 18.66.Found: C, 60.11; H, 5.56; N, 18.51.

Ethyl2-acetamido-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ8). This compound was obtained by reaction of QZQ5 after 2 h. Whitesolid; yield: 79%, mp: 211-212° C.; IR: 3387 (NH), 1700 (CO), 1695 (CO)cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.30 (3H, t, J=7.1 Hz, CH₃), 2.21-2.29(5H, m, CH₃ and CH₂), 2.61 (2H, t, J=6.8 Hz, CH₂), 4.27 (2H, q, J=7.1Hz, CH₂), 4.39 (2H, t, J=6.8 Hz, CH₂), 6.71 (1H, d, J=4.1 Hz, Ar), 6.98(1H, d, J=4.1 Hz, Ar), 8.57 (1H, s, H-4), 10.54 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 14.2 (q), 24.6 (q), 25.5 (t), 30.1 (t), 44.0 (t), 67.9(d), 111.1 (d), 116.9 (d), 124.8 (s), 138.7 (s), 145.1 (s), 156.6 (s),157.4 (s), 158.7 (d), 160.2 (s), 169.1 (s). Anal calcd for C₁₆H₁₈N₄O₃:C, 61.13; H, 5.77; N, 17.82. Found: C, 61.01; H, 5.98; N, 17.64.

Propan-2-yl2-acetamido-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate (QZQ25).This compound was obtained by reaction of QZQ17 after 4 h. White solid;yield: 63%; mp: 242-243° C.; IR: 3199 (NH), 1693 (CO), 1675 (CO) cm⁻¹;¹H nmr (CDCl₃) (ppm): 1.36 (6H, d, J=6.2 Hz, 2×CH₃), 2.59 (3H, s, CH₃),3.08 (2H, t, J=6.8 Hz, CH₂), 4.71 (2H, t, J=6.8 Hz, CH₂), 5.17-5.27 (1H,m, CH), 6.95-7.05 (2H, m, Ar), 8.47 (1H, s, H-4), 8.92 (1H, s, NH); ¹³Cnmr (CDCl₃) (ppm): 22.0 (2×q), 24.5 (t), 25.4 (q), 42.2 (t), 68.1 (d),110.5 (d), 117.4 (d), 117.5 (s), 124.8 (s), 126.4 (s), 138.7 (s), 156.5(d), 156.7 (s), 160.6 (s), 161.1 (s). Anal calcd for C₁₆H₁₈N₄O₃: C,61.13; H, 5.77; N, 17.82. Found: C, 61.24; H, 5.49; N, 17.97.

Propan-2-yl2-acetamido-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ26). This compound was obtained by reaction of QZQ21 after 5 h.white solid; yield: 58%; mp: 211-212° C.; IR: 3388 (NH), 1689 (CO), 1673(CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.36 (6H, d, J=6.2 Hz, 2×CH₃),2.34-2.44 (2H, m, CH₂), 2.54 (3H, s, CH₃), 2.67 (2H, t, J=6.9 Hz, CH₂),4.46 (2H, t, J=6.9 Hz, CH₂), 5.14-5.27 (1H, m, CH), 6.74 (1H, d, J=4.1Hz, Ar), 7.02 (1H, d, J=4.1 Hz, Ar), 8.47 (1H, s, H-4), 8.62 (1H, s,NH); ¹³C nmr (CDCl₃) (ppm): 22.0 (2×q), 25.3 (q), 26.2 (t), 30.8 (t),44.1 (t), 67.9 (t), 111.5 (d), 117.4 (d), 117.5 (s), 124.9 (s), 126.4(s), 138.7 (s), 156.5 (s), 158.4 (d), 158.7 (s), 160.6 (s). Anal calcdfor C₁₇H₂₀N₄O₃: C, 62.18; H, 6.14; N, 17.06. Found: C, 62.03; H, 6.29;N, 15.87.

Scheme 6 describes the general synthesis of pyrazolo[4,3-h]quinolines asreported in Table 6. In addition, the skilled person will recognise thatcompounds of formula 33 as shown in Scheme 6 can be reacted as describedin Scheme 2 for compounds of formula 8 to obtain additional compounds ofthe present invention.

The synthesis of derivatives pyrazolo[4,3-h]quinolines of type 34 wasachieved according to synthetic Scheme 6 starting from ketone 31prepared according to the synthetic procedure by Beria et al J. Med.Chem. 2010, 53, 3532-3551. Functionalization of the pyrazole nitrogenwas obtained with classical procedures in N,N-dimethylformamide (DMF) ortetrahydrofuran (THF) with sodium hydride (NaH) as the base, followed bynucleophilic substitution with aryl halides and alkyl halides giving thecorresponding N-substituted derivatives 32. Direct introduction of theα-enamino functionality using Bredereck's reagent,t-butoxy-bis-(dimethylamino)methane (TBDMAM) gave compounds of formula32 which were subjected to the final cyclization step to 34.

The derivatives reported in Tables 6 below are exemplary compounds thatmay be prepared according to the synthetic procedure of Scheme 6.Relative additivity indeces (AI %), which were measured as described inthe Materials and Methods section, are also reported.

TABLE 6 Pyrazolo[4,3-h]quinolines of formula:

CPD R R² AI (%) ^(a) PZ1 4-MeBn (N-1) COOEt  88% PZ3 3-MeBn (N-1) COOEt163% PZ5 4-BrBn (N-1) COOEt  64% PZ7 3,4-(Me)₂Bn (N-1) COOEt 104% PZ83,4-(Me)₂Bn (N-2) COOEt  21% ^(a) Activity of compounds (at 10 μM) wasexpressed as additivity index (AI %) which is calculated as(QR_(TOT)-QR_(VX))/QR_(VX) where QR_(TOT) is the quenching rate (HS-YFPassay) in the presence of test compound plus VX-809 and QR_(VX) is thequenching rate with VX-809 alone.

A detailed description of the synthesis of exemplary compounds reportedin Scheme 6 is provided hereinbelow.

General Procedure for the Synthesis of ethyl1-substituted-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate 32

To a solution of ethyl7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate 31 (9 mmol) inanhydrous DMF (17 mL), NaH (0.24 g, 10 mmol) was added at 0° C. and thereaction was stirred at room temperature for 1 h. Then the suitablearalkyl halide (13.5 mmol) was added at 0° C. and the reaction mixturewas stirred at room temperature up to completeness (TLC). Then thereaction mixture was poured onto crushed ice. The precipitate wasfiltered and dried, in absence the solution was extracted with DCM (3×50mL). The organic layer was dried (Na₂SO₄) and the solvent was removedunder reduced pressure. The crude product was purified by chromatography(DCM).

Ethyl1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate.This compound was obtained from reaction of 31 with 3-methylbenzylchloride: colorless oil; yield: 48%; IR: 1714 (CO), 1685 (CO) cm⁻¹; ¹Hnmr (CDCl₃) (ppm): 1.41 (3H, t, J=7.1 Hz, CH₃), 2.05-2.18 (2H, m, CH₂),2.30 (3H, s, CH₃), 2.54 (2H, t, J=6.1 Hz, CH₂), 3.03 (2H, t, J=6.1 Hz,CH₂), 4.43 (2H, q, J=7.1 Hz, CH₂), 5.72 (2H, s, CH₂), 7.05-7.27 (4H, m,H-2′, H-4′, H-5′ and H-6′); ¹³C nmr (CDCl₃) (ppm): 14.4 (q), 21.4 (q),21.9 (t), 24.2 (t), 39.3 (t), 55.7 (t), 61.1 (t), 125.2 (d), 128.5 (d),128.8 (d), 128.9 (d), 133.6 (s), 135.4 (s), 135.8 (s), 138.2 (s), 139.0(s), 162.2 (s), 189.3 (s). Anal calcd for C₁₈H₂₀N₂O₃: C, 69.21; H, 6.45;N, 8.97. Found: C, 69.08; H, 6.58; N, 9.09.

Ethyl2-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate.This compound was obtained from reaction of 31 with 3-methylbenzylchloride: colorless oil; yield: 39%; IR: 1718 (CO), 1695 (CO) cm⁻¹; ¹Hnmr (CDCl₃) (ppm): 1.36 (3H, t, J=7.1 Hz, CH₃), 2.08-2.21 (2H, m, CH₂),2.30 (3H, s, CH₃), 2.64 (2H, t, J=6.1 Hz, CH₂), 2.97 (2H, t, J=6.1 Hz,CH₂), 4.34 (2H, q, J=7.1 Hz, CH₂), 5.80 (2H, s, CH₂), 7.05-7.28 (4H, m,H-2′, H-4′, H-5′ and H-6′); ¹³C nmr (CDCl₃) (ppm): 14.2 (q), 21.4 (q),22.3 (t), 23.9 (t), 39.4 (t), 56.3 (t), 61.3 (t), 125.1 (d), 128.4 (d),128.6 (d), 128.8 (d), 129.1 (s), 132.6 (s), 135.9 (s), 138.2 (s), 145.4(s), 159.5 (s), 193.1 (s). Anal calcd for C₁₈H₂₀N₂O₃: C, 69.21; H, 6.45;N, 8.97. Found: C, 69.33; H, 6.32; N, 9.08.

Ethyl1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate.This compound was obtained from reaction of 31 with 4-methylbenzylchloride: colorless oil; yield: 45%; IR: 1721 (CO), 1686 (CO) cm⁻¹; ¹Hnmr (CDCl₃) (ppm): 1.41 (3H, t, J=7.1 Hz, CH₃), 2.07-2.14 (2H, m, CH₂),2.32 (3H, s, CH₃), 2.54 (2H, t, J=6.2 Hz, CH₂), 3.02 (2H, t, J=6.2 Hz,CH₂), 4.42 (2H, q, J=7.1 Hz, CH₂), 5.72 (2H, s, CH₂), 7.09 (2H, d, J=8.0Hz, H-3′ and H-5′), 7.26 (2H, d, J=8.0 Hz, H-2′ and H-6′); ¹³C nmr(CDCl₃) (ppm): 14.4 (q), 21.1 (q), 21.9 (t), 24.2 (t), 39.3 (t), 55.5(t), 61.0 (t), 128.2 (2×d), 129.3 (2×d), 133.0 (s), 133.7 (s), 135.3(s), 137.8 (s), 138.9 (s), 162.1 (s), 189.3 (s). Anal calcd perC₁₈H₂₀N₂O₃: C, 69.21; H, 6.45; N, 8.97. Found: C, 69.10; H, 6.57; N,8.84.

Ethyl2-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate.This compound was obtained from reaction of 31 with 4-methylbenzylchloride: white solid; yield: 25%; m.p.: 107-108° C.; IR: 1718 (CO),1694 (CO) cm⁻¹; ¹H nmr (CDCl₃) (ppm): 1.36 (3H, t, J=7.1 Hz, CH₃),2.07-2.16 (2H, m, CH₂), 2.30 (3H, s, CH₃), 2.63 (2H, t, J=6.2 Hz, CH₂),2.96 (2H, t, J=6.2 Hz, CH₂), 4.34 (2H, q, J=7.1 Hz, CH₂), 5.80 (2H, s,CH₂), 7.10 (2H, d, J=7.9 Hz, H-3′ and H-5′), 7.25 (2H, d, J=7.9 Hz, H-2′and H-6′); ¹³C nmr (CDCl₃) (ppm): 14.2 (q), 21.2 (q), 22.3 (t), 23.9(t), 39.4 (t), 56.1 (t), 61.3 (t), 128.1 (2×d), 129.0 (s), 129.2 (2×d),132.5 (s), 133.0 (s), 137.8 (s), 145.4 (s), 159.5 (s), 193.0 (s). Analcalcd for C₁₈H₂₀N₂O₃: C, 69.21; H, 6.45; N, 8.97. Found: C, 69.08; H,6.56; N, 8.86.

Ethyl1-[(3,4-dimethylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate.This compound was obtained from reaction of 31 with 3,4-dimethylbenzylchloride: white solid; yield: 45%; m.p.: 79-80° C.; IR: 1710 (CO), 1682(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.30 (3H, t, J=7.0 Hz, CH₃),1.96-2.10 (2H, m, CH₂), 2.16 (6H, s, CH₃), 2.54 (2H, t, J=5.6 Hz, CH₂),2.93 (2H, t, J=5.6 Hz, CH₂), 4.29 (2H, q, J=7.0 Hz, CH₂), 5.63 (2H, s,CH₂), 6.90 (1H, d, J=7.6 Hz, H-6′), 7.01 (1H, s, H-1′), 7.06 (1H, d,J=7.6 Hz, H-5′); ¹³C nmr (DMSO-d₆) (ppm): 14.6 (q), 19.4 (q), 19.8 (q),21.8 (t), 24.2 (t), 39.2 (t), 55.0 (t), 60.8 (t), 125.4 (d), 129.2 (d),130.1 (d), 133.4 (s), 134.2 (s), 135.6 (s), 136.3 (s), 136.8 (s), 138.8(s), 161.8 (s), 189.7 (s). Anal calcd for C₁₉H₂₂N₂O₃: C, 69.92; H, 6.79;N, 8.58. Found: C, 70.11; H, 6.58; N, 8.77.

Ethyl2-[(3,4-dimethylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate.This compound was obtained from reaction of 31 with 3,4-dimethylbenzylchloride: white solid; yield: 23%; m.p.: 96-97° C.; IR: 1717 (CO), 1689(CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.30 (3H, t, J=7.1 Hz, CH₃),1.99-2.07 (2H, m, CH₂), 2.16 (6H, s, 2×CH₃), 2.52 (2H, t, J=6.0 Hz,CH₂), 2.90 (2H, t, J=6.0 Hz, CH₂), 4.31 (2H, q, J=7.1 Hz, CH₂), 5.69(2H, s, CH₂), 6.90 (1H, d, J=7.7 Hz, H-6′), 7.02 (1H, s, H-1′), 7.06(1H, d, J=7.7 Hz, H-5′); ¹³C nmr (DMSO-d₆) (ppm): 14.4 (q), 19.4 (q),19.8 (q), 22.1 (t), 23.9 (t), 39.7 (t), 55.6 (t), 61.6 (t), 125.4 (d),129.1 (d), 129.2 (s), 130.0 (d), 132.7 (s), 134.3 (s), 136.3 (s), 136.7(s), 145.5 (s), 159.5 (s), 192.4 (s). Anal calcd for C₁₉H₂₂N₂O₃: C,69.92; H, 6.79; N, 8.58. Found: 69.79; H, 6.64; N, 8.71.

Ethyl1-[(4-bromophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate.This compound was obtained from reaction of 31 with 4-bromobenzylbromide: yellow oil; yield: 51%; IR: 1717 (CO), 1684 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.29 (3H, t, J=7.0 Hz, CH₃), 1.95-2.12 (2H, m, CH₂),2.53 (2H, t, J=5.5 Hz, CH₂), 2.93 (2H, t, J=5.5 Hz, CH₂), 4.29 (2H, q,J=7.0 Hz, CH₂), 5.69 (2H, s, CH₂), 7.15 (2H, d, J=8.0 Hz, H-2′ andH-6′), 7.51 (2H, d, J=8.0 Hz, H-3′ and H-5′); ¹³C nmr (DMSO-d₆) (ppm):14.6 (q), 21.8 (t), 24.2 (t), 39.1 (t), 55.6 (t), 60.9 (t), 121.5 (s),130.2 (2×d), 132.0 (2×d), 133.5 (s), 135.7 (s), 136.2 (s), 139.1 (s),145.6 (s), 161.7 (s), 189.8 (s). Anal calcd for C₁₇H₁₇BrN₂O₃: C, 54.13;H, 4.54; N, 7.43. Found: C, 54.01; H, 4.72; N, 7.56.

Ethyl2-[(4-bromophenyl)methy]-7-oxo-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate.This compound was obtained from reaction of 31 with 4-bromobenzylbromide: yellow oil; yield: 21%; IR: 1718 (CO), 1700 (CO) cm⁻¹; ¹H nmr(DMSO-d₆) (ppm): 1.27 (3H, t, J=7.1 Hz, CH₃), 1.98-2.14 (2H, m, CH₂),2.53 (2H, t, J=5.9 Hz, CH₂), 2.90 (2H, t, J=5.9 Hz, CH₂), 4.29 (2H, q,J=7.0 Hz, CH₂), 5.75 (2H, s, CH₂), 7.15 (2H, d, J=8.2 Hz, H-2′ andH-6′), 7.51 (2H, d, J=8.2 Hz, H-3′ and H-5′); ¹³C nmr (DMSO-d₆) (ppm):14.3 (q), 21.1 (t), 23.9 (t), 39.6 (t), 55.3 (t), 61.7 (t), 121.5 (s),129.4 (s), 130.0 (2×d), 131.9 (2×d), 132.7 (s), 136.4 (s), 145.7 (s),159.4 (s), 192.3 (s). Anal calcd for C₁₇H₁₇BrN₂O₃: C, 54.13; H, 4.54; N,7.43. Found: C, 54.27; H, 4.68; N, 7.31.

General Procedure for the Synthesis of ethyl6-[(dimethylamino)methylidene]-1-Substituted-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylateand ethyl6-[(dimethylamino)methylidene]-2-substituted-7-oxo-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate33

To a solution of 32 (2.6 mmol) in anhydrous toluene (3 mL) TBDMAM (1.61mL, 7.8 mmol) was added and the reaction mixture was heated at reflux upto completeness (TLC). After cooling, the solvent was removed underreduced pressure.

6-[(dimethylamino)methylidene]-1-[(3-methylphenyl)methyl]-1,4,5,6-tetrahydro-7H-indazol-7-one.This compound was obtained by reaction of ethyl1-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylateafter 16 h and used in the next step without further purification.

6-[(dimethylamino)methylidene]-2-[(3-methylphenyl)methyl]-2,4,5,6-tetrahydro-7H-indazol-7-one.This compound was obtained by reaction of ethyl2-[(3-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-2H-indazole-3-carboxylateafter 3 h and used in the next step without further purification.

6-[(dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-1,4,5,6-tetrahydro-7H-indazol-7-one.This compound was obtained by reaction of ethyl1-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylateafter 16 h and used in the next step without further purification.

6-[(dimethylamino)methylidene]-2-[(4-methylphenyl)methyl]-2,4,5,6-tetrahydro-7H-indazol-7-one.This compound was obtained by reaction of ethyl2-[(4-methylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-2H-indazole-3-carboxylateafter 3 h and used in the next step without further purification.

6-[(dimethylamino)methylidene]-1-[(3,4-dimethylphenyl)methyl]-1,4,5,6-tetrahydro-7H-indazol-7-one.This compound was obtained by reaction of ethyl1-[(3,4-dimethylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylateafter 5 h and used in the next step without further purification.

6-[(dimethylamino)methylidene]-2-[(3,4-dimethylphenyl)methyl]-2,4,5,6-tetrahydro-7H-indazol-7-one.This compound was obtained by reaction of ethyl2-[(3,4-dimethylphenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-2H-indazole-3-carboxylateafter 1 h and used in the next step without further purification.

1-[(4-bromophenyl)methyl]-6-[(dimethylamino)methylidene]-1,4,5,6-tetrahydro-7H-indazol-7-one.This compound was obtained by reaction of ethyl1-[(4-bromophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylateafter 5 h and used in the next step without further purification.

2-[(4-bromophenyl)methyl]-6-[(dimethylamino)methylidene]-2,4,5,6-tetrahydro-7H-indazol-7-one.This compound was obtained by reaction of ethyl2-[(4-bromophenyl)methyl]-7-oxo-4,5,6,7-tetrahydro-2H-indazole-3-carboxylateafter 2 h and used in the next step without further purification.

General Procedure for the Synthesis of pyrazolo[4,3-h]quinolinones 34

To a solution of the enamiketones 33 (2.76 mmol) in anhydrous ethanol(20 mL) under nitrogen atmosphere phenylsulfonylacetonitrile was added(0.75 g, 4.14 mmol). The reaction mixture was heated under reflux for 24h. The solvent was removed under reduced pressure. The crude product waspurified by chromatography (DCM/AcOEt 9:1)

Ethyl7-(benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ1). This compound was obtained by reaction of6-[(dimethylamino)methylidene]-1-[(4-methylphenyl)methyl]-1,4,5,6-tetrahydro-7H-indazol-7-one.Light yellow solid; yield: 79%; m.p.: 312-313° C.; IR: 3416 (NH), 1718(CO), 1601 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.30 (3H, t, J=7.1 Hz,CH₃), 2.21 (3H, s, CH₃), 2.99 (4H, s, 2×CH₂), 4.28 (2H, q, J=7.1 Hz,CH₂), 6.01 (2H, s, CH₂), 7.08-7.10 (4H, m, H-2′, H-4′, H-5′ and H-6′),7.62-7.66 (3H, m, H-3″, H-4″ and H-5″), 7.97 (2H, d, J=6.5 Hz, H-2″ andH-6″), 8.26 (1H, s, H-6), 12.20 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):14.1 (q), 19.1 (t), 20.6 (q), 26.7 (t), 54.2 (t), 60.2 (t), 119.2 (s),123.7 (s), 125.5 (s), 127.5 (2×d), 127.9 (2×d), 128.9 (2×d), 129.0(2×d), 133.6 (s), 134.2 (d), 135.8 (s), 136.7 (d), 138.2 (s), 138.9 (s),140.3 (s), 147.8 (s), 158.2 (s), 161.6 (s). Anal calcd for C₂₇H₂₅N₃O₅S:C, 64.40; H, 5.00; N, 8.34. Found: C, 64.51; H, 4.90; N, 8.45.

Ethyl7-(benzenesulfonyl)-2-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ2). This compound was obtained by reaction of6-[(dimethylamino)methylidene]-2-[(4-methylphenyl)methyl]-2,4,5,6-tetrahydro-7H-indazol-7-one.Yellow solid; yield: 81%; m.p.: 201-202° C.; IR: 3233 (NH), 1718 (CO),1664 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.29 (3H, t, J=7.0 Hz, CH₃),2.24 (3H, s, CH₃), 2.88-2.96 (4H, m, 2×CH₂), 4.29 (2H, q, J=7.0 Hz,CH₂), 5.69 (2H, s, CH₂), 6.98-7.11 (4H, m, H-2′, H-4′, H-5′ and H-6′),7.55-7.69 (3H, m, H-3″, H-4″ and H-5″), 7.98 (2H, d, J=6.9 Hz, H-2″ andH-6″), 8.29 (1H, s, H-6), 12.62 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):13.9 (q), 19.4 (t), 20.6 (q), 25.1 (t), 54.9 (t), 61.3 (t), 114.2 (s),125.9 (s), 127.2 (2×d), 128.1 (2×d), 128.7 (2×d), 128.8 (s), 128.9 (s),129.0 (2×d), 129.0 (s), 133.3 (d), 133.7 (s), 133.8 (d), 136.9 (s),140.2 (s), 141.9 (s), 157.1 (s), 158.9 (s). Anal calcd for C₂₇H₂₅N₃O₅S:C, 64.40; H, 5.00; N, 8.34. Found: C, 64.28; H, 5.13; N, 8.21.

Ethyl7-(benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ3). This compound was obtained by reaction of6-[(dimethylamino)methylidene]-1-[(3-methylphenyl)methyl]-1,4,5,6-tetrahydro-7H-indazol-7-one.White solid; yield: 87%; m.p.: 269-270° C.; IR: 3176 (NH), 1700 (CO),1697 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.30 (3H, t, J=7.1 Hz, CH₃),2.20 (3H, s, CH₃), 3.00 (4H, s, 2×CH₂), 4.28 (2H, q, J=7.1 Hz, CH₂),6.03 (2H, s, CH₂), 6.95-7.18 (4H, m, H-2′, H-4′, H-5′ and H-6′),7.59-7.75 (3H, m, H-3″, H-4″ and H-5″), 7.97 (2H, d, J=6.8 Hz, H-2″ andH-6″), 8.27 (1H, s, H-6), 12.71 (1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm):14.1 (q), 19.1 (t), 20.9 (q), 26.6 (t), 54.3 (t), 60.2 (t), 119.3 (s),123.8 (s), 124.5 (d), 125.4 (s), 128.0 (2×d), 128.1 (d), 128.2 (d),128.4 (d), 129.0 (2×d), 135.6 (d), 135.9 (s), 137.2 (s), 137.5 (s),138.3 (s), 138.9 (d), 140.3 (s), 147.8 (s), 158.1 (s), 161.6 (s). Analcalcd for C₂₇H₂₅N₃O₅S: C, 64.40; H, 5.00; N, 8.34. Found: C, 64.52; H,4.87; N, 8.42.

Ethyl7-(benzenesulfonyl)-2-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ4). This compound was obtained by reaction of6-[(dimethylamino)methylidene]-2-[(3-methylphenyl)methyl]-2,4,5,6-tetrahydro-7H-indazol-7-one.Light brown solid; yield: 83%; m.p.: 225-226° C.; IR: 3233 (NH), 1721(CO), 1699 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.28 (3H, t, J=6.9 Hz,CH₃), 2.24 (3H, s, CH₃), 2.89-2.97 (4H, m, 2×CH₂), 4.30 (2H, q, J=6.9Hz, CH₂), 5.70 (2H, s, CH₂), 6.97-7.21 (4H, m, H-2′, H-4′, H-5′ andH-6′), 7.57-7.70 (3H, m, H-3″, H-4″ and H-5″), 7.98 (2H, d, J=7.4 Hz,H-2″ and H-6″), 8.29 (1H, s, H-6), 12.61 (1H, s, NH); ¹³C nmr (DMSO-d₆)(ppm): 14.4 (q), 19.8 (t), 21.4 (q), 25.6 (t), 55.5 (t), 61.7 (t), 124.4(s), 124.8 (d), 126.4 (s), 128.2 (d), 128.6 (2×d), 128.8 (d), 128.9 (d),129.2 (2×d), 129.5 (s), 133.8 (d), 137.1 (s), 137.2 (s), 138.1 (s),138.2 (s), 140.7 (s), 141.5 (s), 144.0 (d), 157.5 (s), 159.4 (s). Analcalcd for C₂₇H₂₅N₃O₅S: C, 64.40; H, 5.00; N, 8.34. Found: 64.56; H,4.88; N, 8.23.

Ethyl7-(benzenesulfonyl)-1-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ5). This compound was obtained by reaction of1-[(4-bromophenyl)methyl]-6-[(dimethylamino)methylidene]-1,4,5,6-tetrahydro-7H-indazol-7-one.White solid; yield: 85%; m.p.: 304-305° C.; IR: 3405 (NH), 1736 (CO),1716 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.29 (3H, t, J=7.1 Hz, CH₃),3.00 (4H, s, 2×CH₂), 4.28 (2H, q, J=7.1 Hz, CH₂), 6.03 (2H, s, CH₂),7.19 (2H, d, J=8.2 Hz, H-2′ and H-6′), 7.48 (2H, d, J=8.1 Hz, H-3′ andH-5′), 7.60-7.74 (3H, m, H-3″, H-4″ and H-5″), 7.96 (2H, d, J=7.3 Hz,H-2″ and H-6″), 8.26 (1H, s, H-6), 12.20 (1H, s, NH); ¹³C nmr (DMSO-d₆)(ppm): 14.6 (q), 19.6 (t), 27.1 (t), 54.2 (t), 60.8 (t), 119.9 (s),121.3 (s), 124.4 (s), 125.9 (s), 128.5 (2×d), 129.5 (2×d), 130.3 (2×d),131.9 (2×d), 134.1 (d), 136.4 (s), 137.1 (d), 139.0 (s), 139.4 (s),140.8 (s), 148.2 (s), 158.7 (s), 162.0 (s). Anal calcd forC₂₆H₂₂BrN₃O₅S: C, 54.94; H, 3.90; N, 7.39. Found: 54.79; H, 4.08; N,7.52.

Ethyl7-(benzenesulfonyl)-2-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ6). This compound was obtained by reaction of1-[(4-bromophenyl)methyl]-6-[(dimethylamino)methylidene]-1,4,5,6-tetrahydro-7H-indazol-7-one.Yellow solid; yield: 77%; m.p.: 268-269° C.; IR: 3216 (NH), 1715 (CO),1675 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.28 (3H, t, J=7.1 Hz, CH₃),2.89-2.97 (4H, m, 2×CH₂), 4.28 (2H, q, J=7.1 Hz, CH₂), 5.71 (2H, s,CH₂), 7.17 (2H, d, J=8.1 Hz, H-2′ and H-6′), 7.51 (2H, d, J=8.1 Hz, H-3′and H-5′), 7.56-7.70 (3H, m, H-3″, H-4″ and H-5″), 7.97 (2H, d, J=7.9Hz, H-2″ and H-6″), 8.29 (1H, s, H-6), 12.59 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 14.3 (q), 19.8 (t), 25.5 (t), 55.0 (t), 61.8 (t), 109.4(s), 107.9 (s), 121.3 (s), 124.2 (s), 126.4 (s), 128.6 (2×d), 129.2(2×d), 129.5 (s), 129.9 (2×d), 131.7 (s), 131.9 (2×d), 133.8 (d), 136.7(s), 140.7 (s), 157.4 (s), 159.4 (s). Anal calcd for C₂₆H₂₂BrN₃O₅S: C,54.94; H, 3.90; N, 7.39. Found: 55.10; H, 3.75; N, 7.51.

Ethyl7-(benzenesulfonyl)-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ7). This compound was obtained by reaction of6-[(dimethylamino)methylidene]-1-[(3,4-dimethylphenyl)methyl]-1,4,5,6-tetrahydro-7H-indazol-7-one.White solid; yield: 78%; m.p.: 260-261° C.; IR: 3405 (NH), 1738 (CO),1592 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.29 (3H, t, J=7.1 Hz, CH₃),2.09 (3H, s, CH₃), 2.11 (3H, s, CH₃), 2.98 (4H, s, 2×CH₂), 4.28 (2H, q,J=7.1 Hz, CH₂), 5.96 (2H, s, CH₂), 6.89 (1H, d, J=7.5 Hz, H-6′), 6.96(2H, d, J=7.3 Hz, H-2′ and H-5′), 7.59-7.73 (3H, m, H-3″, H-4″ andH-5″), 7.96 (2H, d, J=7.3 Hz, H-2″ and H-6″), 8.25 (1H, s, H-6), 12.19(1H, s, NH); ¹³C nmr (DMSO-d₆) (ppm): 14.6 (q), 19.4 (q), 19.6 (q), 19.8(t), 27.2 (t), 54.7 (t), 60.7 (t), 119.7 (s), 124.3 (s), 125.4 (d),126.0 (s), 128.5 (2×d), 129.2 (d), 129.5 (2×d), 129.9 (d), 134.1 (d),135.0 (s), 136.0 (s), 136.3 (d), 136.5 (s), 138.6 (s), 139.4 (s), 140.9(s), 148.4 (s), 158.6 (s), 162.1 (s). Anal calcd for C₂₈H₂₇N₃O₅S: C,64.97; H, 5.26; N, 8.12. Found: 65.09; H, 5.14; N, 8.01.

Ethyl7-(benzenesulfonyl)-2-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ8). This compound was obtained by reaction of6-[(dimethylamino)methylidene]-2-[(3,4-dimethylphenyl)methyl]-1,4,5,6-tetrahydro-7H-indazol-7-one.Yellow solid; yield: 87%; m.p.: 220-221° C.; IR: 3228 (NH), 1718 (CO),1670 (CO) cm⁻¹; ¹H nmr (DMSO-d₆) (ppm): 1.29 (3H, t, J=7.1 Hz, CH₃),2.15 (6H, s, 2×CH₃), 2.80-3.04 (4H, m, 2×CH₂), 4.30 (2H, q, J=7.1 Hz,CH₂), 5.66 (2H, s, CH₂), 6.91 (1H, d, J=7.6 Hz, H-6′), 7.03-7.06 (2H, m,H-2′ and H-5′), 7.57-7.60 (3H, m, H-3″, H-4″ and H-5″), 7.97 (2H, d,J=8.1 Hz, H-2″ and H-6″), 8.28 (1H, s, H-6), 12.53 (1H, s, NH); ¹³C nmr(DMSO-d₆) (ppm): 14.4 (q), 19.4 (2×q), 19.9 (t), 25.5 (t), 55.4 (t),61.7 (t), 103.7 (s), 109.8 (s), 112.8 (s), 125.2 (d), 126.4 (s), 128.1(s), 128.6 (2×d), 128.9 (d), 129.2 (2×d), 129.3 (s), 130.0 (d), 133.8(d), 134.6 (s), 136.2 (s), 136.7 (s), 140.7 (s), 149.6 (d), 157.5 (s),159.4 (s). Anal calcd for C₂₈H₂₇N₃O₅S: C, 64.97; H, 5.26; N, 8.12.Found: 65.12; H, 5.08; N, 8.29.

Biological Data

The complete set of compounds including those reported in Tables 1-6 wassubjected to functional assays in heterologous cells (CFBE41o−) withF508del-CFTR protein expression. The most active compounds were testedon primary airway epithelial cells obtained from patients homozygous forthe F508del mutation, upon obtaining informed consent.

Materials and Methods Evaluation of CFTR Function by KineticFluorescence Assay

CFBE41o− cells, with expression of F508del-CFTR and halogen-sensitivefluorescent protein, were generated as previously described (Sondo E, etal. Am J Physiol. 2011, 301, C872-C885). For the test, the cells wereseeded in 96-well microplates using a culture medium consisting of DMEMand Ham's F12 (1:1) supplemented with 10% foetal bovine serum. After 24hours from seeding, the cells were treated for another 24 hours with thetest compounds dissolved in the culture medium at the desiredconcentrations. As a negative control, the solvent of the compounds(dimethyl sulfoxide, DMSO) dissolved in the medium with the samedilution ratio (final percentage of DMSO:0.1-0.2%) was used. As apositive control, the corrector VX-809 (Selleck Chemicals, S1565) wasused at a concentration of 1 μM. After treatment, the medium with thecompounds was removed and the cells were stimulated with forskolin(Sigma-Aldrich, F6886) 20 μM plus genistein (Sigma-Aldrich, G6649) 50 μM(in 60 μl of PBS saline) to maximally activate the CFTR channels presentin the membrane. In a microplate reader (FLUOstar-Omega, BMG) thefluorescence of the cells in each well was read for 14 seconds, with aninjection of 165 μl of a iodide-enriched saline (modified PBS whereNaCl, 137 mM, has been replaced with the same concentration of NaI). Theiodide transport activity in each well was evaluated by subtraction ofthe background fluorescence (measured in a well without cells),subsequent normalization with respect to the initial fluorescence andfinally by interpolation of the fluorescence quenching phase with anexponential function that allows the derivation of the maximum slope(quenching rate, QR).

To assess the function and pharmacological sensitivity of G542X-CFTRmutant, inventors used the null version of CFBE41o− cells, i.e. cellswith negligible expression of endogenous CFTR and without HS-YFP. Suchcells were transiently transfected with the plasmid coding for HS-YFPalone or in combination with: empty plasmid, plasmid coding for wildtype CFTR, or plasmid coding for G542X-CFTR. For transfection, cellswere seeded in 96-well microplates (30,000 cells/well) in 150 μl ofantibiotic-free culture medium. After 24 hours, cells were transfectedwith the desired plasmids. For each well, 0.2 μg of total plasmid DNAand 0.5 μl of Lipofectamine 2000 (Invitrogen) were first pre-mixed in 50μl of OPTIMEM (Invitrogen) to generate transfection complexes (60minutes at room temperature), and then added to the cells. After 24hour, the complexes were removed by replacement with fresh culturemedium. The HS-YFP functional assay was performed after further 24hours.

Evaluation of the Transepithelial Ionic Current

The culture and functional study of human primary nasal and bronchialepithelial cells have been described in detail above (Scudieri P, et al.J Physiol. 2012, 590, 6141-6155). Briefly, nasal epithelial cells weretaken after informed consent using the “brushing” technique. Bronchialcells were instead obtained by proteolytic digestion of bronchi isolatedfrom the lungs of patients (suffering from CF or other pulmonarypathology (idiopathic pulmonary fibrosis, pulmonary hypertension,emphysema) subjected to transplant operations. The informed consent ofthe patients was obtained also in this case. After isolation, epithelialcells were cultured in a liquid medium of defined serum-freecomposition. This medium consists of a mixture of LHC9/RPMI 1640 (1:1)enriched with various hormones and growth factors (Scudieri P, et al. JPhysiol. 2012, 590, 6141-6155). After 3-5 passages, necessary for theexpansion of the initial number, the cells were seeded at high densityon Snapwell porous supports (Corning, 3801). After 24 hours, the culturemedium was replaced by a mixture consisting of DMEM and Ham's F12 (1:1)enriched with 2% foetal bovine serum and other supplements. After 5-6days from seeding, the cells were put in an “air-liquid interface”condition, i.e. by removing the culture medium from the apical side. Inthis way the mucociliary differentiation is promoted with the formationof an epithelium provided with high electrical resistance. Forfunctional evaluations, carried out 12-14 days after seeding, theSnapwell supports were inserted into vertical diffusion chambers inwhich the two compartments, apical and basolateral, were filled withsaline solution and connected by Ag/AgCl electrodes to an epithelialVoltage Clamp (EVC-4000, World Precision Instruments). Transepithelialion transport recordings were performed in the short-circuit currentconfiguration. With this mode, the transepithelial potential differenceis locked to zero and the resulting current, supplied by the VoltageClamp is recorded by an AD/DA converter (PowerLab, ADInstruments).

Analysis of F508del-CFTR Maturation by Immunoblot

CFBE41o− cells were grown to confluence on 60-mm diameter dishes andlysed in RIPA buffer containing a complete protease inhibitor (Roche;cat. n. 11697498001). Cell lysates were centrifuged at 12000 rpm at 4°C. for 10 min. Supernatant protein concentration was calculated usingthe BCA assay (Euroclone; cat. n. EMP014500) following themanufacturer's instructions. Equal amounts of total protein content (30μg) were separated onto 10% Criterion TGX Precast gels (Bio-radlaboratories Inc.; cat. n. 4561033), transferred to nitrocellulosemembrane with Trans-Blot Turbo system (Bio-rad Laboratories Inc.) andanalyzed by Western blotting. Primary antibody for CFTR was anti-CFTR596 (University of North Carolina at Chapel Hill, and Cystic FibrosisFoundation Therapeutics, see Cui L, et al. J. Mol Biol 2007, 365,981-994) at 1:5000 dilution. As secondary antibody, anti-mouseHRP-conjugated Ab 97023 (Abcam) was used at 1:10000 dilution. Resultswere subsequently visualized by chemiluminescence using the SuperSignalWest Femto Substrate (Thermo Scientific) and the Molecular ImagerChemiDoc XRS System.

Analysis of F508del-CFTR Localization by Immunofluorescence

CFBE41o− cells were seeded in a 12-well μ-chamber (81201, Ibidi) at adensity of 25.000 cells per well and treated with compounds for 24 hr.Cells were then rinsed with PBS and fixed by adding 100 μl per well of10% neutral buffered formalin for 5 minutes at room temperature. After 3washes with 300 μl of PBS, cells were permeabilized with PBS-TritonX-100 0.3% for 5 min, blocked with PBS-BSA 1% for 2 hr, and incubatedovernight at 4° C. with 100 μl of primary antibody diluted in blockingsolution. The CFTR antibody was ab570 mouse IgG1 (University of NorthCarolina at Chapel Hill, and Cystic Fibrosis Foundation Therapeutics,see Cui L, et al. J. Mol Biol 2007, 365, 981-994) diluted at 1:250.Following incubation with primary antibody, cells were rinsed threetimes with PBS and incubated with 100 μl of a solution of secondary goatanti-mouse Alexa Fluor-546 antibodies (Invitrogen A-11030) diluted inPBS-BSA 1% for 1 hour in the dark. After three further washes in PBS,cells were covered with mounting medium and coverslip, and then analysedusing a laser-scanning confocal microscope SPE (Leica Microsystems).

Results Structure-Activity Relationship

As reported in the above tables, the “additivity index” (AI) was used asa parameter to report the ability of the compounds of the invention tosynergize with class 1 correctors such as VX-809. In the example of FIG.1, the AI of PP007 at 10 μM is 74%.

It is noted that in the pyrrolo[3,2-h]quinolinone series 1, the potencyorder is: P007 (R=4-MeBn R²=H)>PP011 (R=Bn R²=H)>PP010 (R=Me R²=H),indicating that the absence of the 4-methyl group in benzyl (PP011) orthe substitution with a small alkyl group such as methyl (PP010) causesa reduction in activity. The introduction of a bromine atom in thetricyclic scaffold at position 7 determines an important increase inpotency, leading to one of the most active derivatives of the seriesPP008 (R=4-MeBn R²=Br).

In both classes of compounds (pyrrolo[3,2-h]quinolinone 1 andheterocyclic pyrrole[3′,2′:6,7]cyclohepta[1,2-b]pyridine 2), the bromoderivatives PP008 and PP056 are more potent than the non-halogenatedanalogues PP007 and PP048 respectively.

Focusing on the substituent R, the compounds PP015 (R=2-MeBn) and PP016(R=3-MeBn) were synthesized. These compounds present a methyl displacedfrom the original 4-benzyl position at the new 2- and 3-benzyl positionsrespectively; PP017 (R=4-ClBn), in which the 4-MeBn substituent wasreplaced with a 4-Clbenzyl to evaluate the different electronic effectof the chlorine atom in the same position of the benzyl system on theactivity. Furthermore, the dimethyl benzyl derivatives PP021(R=2.4-diMeBn) and PP025 (R=3.4-diMeBn) in which, in addition to themethyl at position 4, there is an additional methyl at position 2 and 3respectively, were prepared to evaluate the possible additive effect ofthe methyl group at ortho and meta benzyl positions. All the derivativeswere then converted into their brominated analogues PP027, PP028, PP029respectively, and PP033, PP037 for dimethyls. Methoxy esters PP019(R=4-MeBn), PP020 (R=2-MeBn), and isopropyl PP022 and their bromoderivatives PP032, PP031, PP034 respectively, were considered.

Referring to the substituent R3, the effect of introducing a chlorineatom or a methyl group at position 4 of the phenylsulfonyl group PP018(R3=4-ClSO₂Ph) and PP023 (R³=4-MeSO₂Ph) and 4-methyl sulfonyl PP024(R3=4-MeSO₂) and their bromine analogues PP030, PP035 and PP036 (R²=Br)respectively, was evaluated.

The 2-Me benzyl substituent produces a derivative (PP027) with potencycomparable to that of PP008. Significant results were obtained for thePP028 derivative in which the methyl was moved to the benzyl position 3,with an important increase in efficiency in combination with the VX-809and potency, even compared to PP008. The role of the 3-methylsubstituent is also evident in the two N-dimethylbenzyl substitutedpyrrole quinolinones. In fact, while for PP033 2,4 dimethyl benzyl thereis a reduction in activity compared to PP008, for PP037, where the twomethyls are simultaneously present at the positions 3,4, which hadalready proved to be the best, a marked activity is obtained with anincrease in potency compared to PP008. Increased activity is alsoobtained switching to the isopropyl ester (R′) keeping the 4-methylbenzyl substituent on the pyrrole nitrogen (compare PP034 with PP008)and for the aromatic analogue derivative PP057 of P008.

Evaluation of the Corrective Activity of the Compounds of the Inventionin CFBE41o− Cells

The activity of the synthesized compounds was initially evaluated on theCFBE41o− cell line with expression of the mutated F508del-CFTR proteindescribed above (Sondo E, et al. Am J Physiol. 2011, 301, C872-C885).For this purpose, a functional assay based on the fluorescent YFPprotein sensitive to halides, HS-YFP, was used (Galietta L J, et al. JBiol Chem. 2001, 276, 19723-19728). The fluorescence of the HS-YFPprotein is turned off by iodide. Therefore, if exposed to a solutioncontaining iodide, cells with HS-YFP expression show a quenching speedof the fluorescence which depends on the presence and activity ofanionic channels. Under control conditions, the mutated CFTR proteinpresents a serious defect of stability and maturation, so it remainstrapped in the endoplasmic reticulum not reaching the cell surface inenough quantity. In the HS-YFP-based assay, this defect results in a lowanion transport capacity and therefore in a low quenching rate (QR).Treatment for a prolonged time (e.g. 24 hours) with a correctordetermines an improvement in protein maturation with an increase in thenumber of CFTR channels present in the membrane and therefore anincrease in the flux of iodide and QR.

In a first phase, the authors screened about 200 heterocyclic moleculeswith various nitrogenated tricyclic scaffolds. Conditions previouslydescribed have been used for screening (Sondo E, et al. Am J Physiol.2011, 301, C872-C885) and reported herein in the Materials and Methodssection. A threshold equal to the average value plus three times thestandard deviation of the QR of wells without compounds (only DMSO inthe culture medium) was used as a criterion for the selection of activecompounds.

After the screening, only one compound was active, PP007. This compoundwas tested again on the same cells at different concentrations, eitheralone or in combination with the corrector VX-809 (1 μM). The plot inFIG. 1 shows the results. Compared to cells under control conditions(cells treated with DMSO alone in the culture medium), the compoundcauses a significant increase in F508del-CFTR activity. This effect isparticularly evident in cells treated with the combination PP007/VX-809.In fact, the net result of the combination is greater than the sum ofthe single effects, thus demonstrating a synergistic mechanism ofaction.

Following the promising results obtained with PP007, compounds with asimilar structure were analysed. The plots in FIG. 2 show the resultobtained with PP007 and analogues thereof at the concentrations of 1 and10 μM, in the presence and absence of the corrector VX-809. Variouscompounds exhibit significant corrective activity when administered tothe cells alone and especially if combined with VX-809. The effect ofthe combination is particularly evident at 10 μM concentration, at whichsome compounds amplify the effect of VX-809 by 3-4 times.

Evaluation of the Corrective Activity of the Compounds of the Inventionin Bronchial and Nasal Epithelial Cells

To further confirm the corrective capacity of the compounds of thepresent invention, the compound PP008, one of the most active molecules,was tested on bronchial and nasal epithelial cells of CF patients withthe F508del mutation in homozygosity (FIG. 3).

The cells were grown in such a way as to generate differentiatedepithelia on porous supports (Snapwell). The epithelia were then studiedin Ussing chamber experiments in short-circuit conditions for theevaluation of the F508del-CFTR protein function (Sondo E, et al. Am JPhysiol 2011, 301, C872-C885). As a channel-protein able to mediate achloride ion flux, CFTR activity is detected as a transepithelial ioniccurrent. In such experiments, we proceed by first blocking the ENaCsodium channel with amiloride (10 μM; Sigma-Aldrich, A7410) and thenmaximally stimulating the CFTR protein with a cAMP analogue (CPT-cAMP;Sigma-Aldrich, C3912) and with the VX-770 potentiator (1 μM; SelleckChemicals, S1144). The potentiator is given to the cells acutely duringrecording (see trace); the corrector is added to the culture medium,kept for 24 hours and then removed. After activation, the CFTR proteinis blocked with a specific inhibitor (inh-172 10 μM; Selleck Chemicals,S7139). Precisely it was the amplitude of the current drop induced byinh-172 which is associated with the levels of F508del-CFTR protein inthe plasma membrane (apical), and therefore reveal the possible activityof corrective compounds. After 24-hour incubation, compound PP008 (10μM) produced a significant increase in current in bronchial cellsblocked by inh-172 (FIG. 3A, B). This increase was even greater when thecells were treated with the PP008 combination plus VX-809 (1 μM). Itshould be noted that the effect of the combination is significantlygreater than the sum of the effects of the individual correctors (FIG.3A, B).

Furthermore, the activity value of F508del-CFTR obtained from thecombination (about 12 μA/cm²) is greater than 50% of the value measuredin bronchial epithelial cells of control subjects (transplanted patientsfor non-CF pathology) with normal CFTR expression.

The synergistic effect obtained with the combination of PP008 withVX-809 was also confirmed in nasal epithelial cells obtained from FCpatients homozygous for the mutation F508del (FIG. 3C).

Comparison of the Compounds of the Invention with Trimethylangelicin(TMA)

The activity of PP008 was compared with that of trimethylangelicin(TMA), a compound described as a very effective corrector of the mutatedCFTR protein.

The results are shown in FIG. 4. TMA was tested at sub micromolarconcentrations (50-500 nM), for which corrective activity was reported(Favia M, et al. Am J Physiol 2014, 307, L48-L61). Higher concentrations(1 and 10 μM) have also been tested to allow comparison with PP008.

The result shown in the plot, rather unexpectedly, reveals that the TMAis ineffective at all concentrations. The negative results obtained withTMA suggest that its activity is strongly influenced by the cellularcontext and/or experimental conditions. The present data indicate thatthe corrective effect of PP008 and its active analogues has a differentmechanism of action than that reported for TMA, despite a certainstructural similarity. In this regard it should be noted that accordingto other authors TMA does not increase the effect of VX-809 (Laselva O,et al. Biochem Pharmacol 2016, 119, 85-92) while in the presentexperiment there is a strong synergistic effect produced by thecombination PP008/VX-809.

The compounds of the present invention offer various advantages in thatthey present a corrective activity of the mutant F508del-CFTR both incell lines and primary cultures of bronchial and nasal epithelial cellsof CF patients. Furthermore, the compounds exhibit a high synergisticaction in combination with the compound VX-809 (lumacaftor).

The present invention has been illustrated and described in a preferredform of practical embodiment, but it is understood that exclusivevariants can be basically applied thereto, yet without departing fromthe scope of industrial protection.

Evaluation of Compounds on F508del-CFTR Protein Maturation andTrafficking

To analyze the mechanism of action of the compounds of the invention,two types of experiments were carried out. In the first type ofexperiment, the electrophoretic mobility of F508del-CFTR protein wasdetermined by immunoblot assay. This is a frequently used method toassess the effect of correctors at the protein level. In controlconditions, F508del-CFTR migrates predominantly as a single band of 150kDa called “band B”. This is the immature form of the protein residingin the endoplasmic reticulum. When the protein folding and stability isimproved by correctors, an additional band appears at higher molecularweight (170 kDa). This is the so-called band C, which represents themature form of the CFTR protein that has reached the Golgi compartmentand acquired full glycosylation.

As shown in FIG. 5, treatment of cells with VX-809 causes appearance ofband C in cell lysates. In agreement with results from functionalassays, treatment of cells with combinations of VX-809 plus compounds ofthe present invention (PP008, PP028, or PP034) resulted in a markedincrease in band C expression with respect to cells treated with VX-809alone.

As a second type of experiment, the localization of F508del-CFTR proteinwas evaluated by immunofluorescence. Cells were treated with compounds,then fixed and immunostained with antibodies against CFTR. Images weretaken with a confocal microscope. FIG. 6 shows that, in untreated cells,F508del-CFTR protein is essentially intracellular. After treatment withVX-809, the protein is still largely expressed in intracellularcompartments. However, combinations of VX-809 with active compounds ofthe present invention (PP028 in the example of FIG. 6) cause appearanceof F508del-CFTR at the cell periphery, in agreement with improvedtrafficking to the plasma membrane.

In conclusion, results obtained by immunoblot (FIG. 6) andimmunofluoresence (FIG. 6) indicate that the marked functional rescue ofF508del-CFTR by compounds of the present invention (FIGS. 1-3) is due toimproved maturation and trafficking of the protein.

Effect of Compounds on G542X-CFTR

To assess the ability of compounds of present invention to improve therescue of premature stop codon (class I) mutations, we carried outexperiments on G542X-CFTR (FIG. 7). Null CFBE41o− cells, devoid ofendogenous CFTR expression, were transiently transfected with empty,wild type CFTR or G542X-CFTR plasmids. All cells also received theHS-YFP plasmid to allow functional determination of CFTR-dependent aniontransport. FIG. 7 shows results obtained from such experiments. Whereindicated, cells with G542X-CFTR were also treated with G418 (0.5 mg/ml)for 24 hr to induce readthrough of the stop codon mutation, with andwithout correctors (VX-809 and/or PP028, labeled as VX and PP). Asexpected, treatment with G418 caused a modest but significant increasein CFTR activity (QR) resulting from readthrough activity, i.e.synthesis of full length CFTR protein. Importantly, co-treatment ofcells with G418 plus VX-809 or PP028 further increased activity withrespected to G418 alone. In particular, PP028 appeared significantlymore effective than VX-809. The activity resulting from wild type CFTRis also shown for comparison.

1. A method for the treatment and/or prevention of a pathologyassociated with a defect in an ABC (ATP-binding cassette) transporterand/or for use in the treatment and/or prevention of a pathologyassociated with at least one of the following: protein mutation, proteinmisfolding, protein degradation, protein maturation, proteintrafficking, comprising administering to a patient in need thereof acompound of general formula (I):

wherein: A is a pentatomic or hexatomic aromatic heterocyclic ring,comprising one, two or three heteroatoms selected from nitrogen, oxygenand sulfur; R is selected from the group consisting of: hydrogen, linearor branched C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, arylsulfonyl, halogen and alkylamine,wherein said linear or branched C1-C6 alkyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, arylsulfonyl oralkylamine is optionally substituted with one or more substituentsindependently selected from: linear or branched C1-C6 alkyl, nitro,amino, halogen, haloalkyl and alkoxy; R¹ and R² are independentlyselected from the group consisting of: hydrogen, carboxylic acid,carboxylic ester, carboxamide from primary, secondary or tertiary amine,halogen, nitro, amine, azide, alkylamine, arylalkyl and trifluoroalkyl,wherein said carboxylic acid, carboxylic ester, carboxamide fromprimary, secondary or tertiary amine, halogen, nitro, amine, azide,alkylamine or trifluorolalkyl is optionally substituted with one or moresubstituents independently selected from: linear or branched C1-C6alkyl, cycloalkyl, nitro, amino, halogen, arylsulfonyl, optionallysubstituted heteroaryl and haloalkyl; R³ is absent or present and isselected from the group consisting of: carbonitrile, carboxylic ester,carboxamide, alkylsulfonyl, arylsulfonyl, wherein said carboxylic ester,carboxamide, alkylsulfonyl or arylsulfonyl is optionally substitutedwith one or more substituents independently selected selected from:linear or branched C1-C6 alkyl, nitro, amino, halogen and haloalkyl; Bis a cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring, wherein saidheterocycloalkyl or heteroaryl ring comprises at least one heteroatomselected from nitrogen, oxygen and sulfur; R⁴ is selected from the groupconsisting of: hydrogen, alkyl, aryl, arylalkyl and heteroaryl; X isselected from the group consisting of: C═O, C—O-alkyl, andC—NR^(a)R^(b); R^(a) and R^(b) are independently selected from the groupconsisting of: hydrogen, alkyl, cycloalkane, aryl, arylalkyl,heteroaryl, heteroarylalkyl, acetyl, arylsulfonyl; wherein said alkyl,cycloalkane, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acetyl orarylsulfonyl is optionally substituted with one or more substituentsindependently selected from: C1-C6 alkyl, nitro, amino, halogen andhaloalkyl; Y is absent or present and is selected from the groupconsisting of: hydrogen, alkyl, aryl and alkylamine; wherein when X isC—O-alkyl or C—NR^(a)R^(b), Y is absent; Q is a carbon or nitrogen atom,wherein when Q is a nitrogen atom, R³ is absent; n is 0, 1, 2 or 3; m is1 or 2; or a pharmaceutically acceptable salt, tautomer, stereoisomer,deuterated derivative, active metabolite thereof.
 2. The methodaccording to claim 1, wherein R⁴ is hydrogen.
 3. The method according toclaim 1, wherein m is
 1. 4. The method according to claim 1, wherein Bis a cycloalkyl or aryl ring, preferably B is cyclohexyl, cycloheptyl orphenyl.
 5. The method according to claim 1, wherein n is 1 or
 2. 6. Themethod according to claim 1, wherein A is a pentatomic aromaticheterocyclic ring comprising one or two nitrogen atoms, preferably A isselected from the group consisting of:


7. The method according to claim 1, wherein X is C═O, C—OMe, C—NH₂ orC—NHR^(a).
 8. The method according to claim 1, wherein: Q is a carbonatom, X is C═O and Y is hydrogen or alkyl, or Q is a carbon atom, X isC—Oalkyl and Y is absent, or Q is a nitrogen atom, X is C—NR^(a)R^(b)and Y is absent.
 9. The method according to claim 1 having one of thefollowing general formulas:


10. The method according to claim 1, wherein R¹ and/or R² is acarboxylic ester or a carboxamide from primary, secondary or tertiaryamine.
 11. The method according to claim 1, wherein R² is halogen. 12.The method according to claim 1, wherein R³ is arylsulfonyl or R³ isabsent, Q is a nitrogen atom, X is C—NR^(a)R^(b), R^(a) is H and R^(b)is arylsulfonyl.
 13. The method according to claim 1, wherein thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt, tautomer, stereoisomer,deuterated derivative, active metabolite thereof.
 14. (canceled)
 15. Themethod according to claim 1, wherein said ABC (ATP-binding cassette)transporter is CFTR (Cystic Fibrosis Transmembrane conductanceRegulator).
 16. The method according to claim 1, wherein said pathologyis selected from the group consisting of: cystic fibrosis, Limb-Girdlemuscular dystrophy (LGMD), Congenital Bilateral Absence of Vas Deferens(CBAVD), acute, chronic, recurrent and/or autoimmune pancreatitis,disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis,smoking-related lung pathology, dry eye syndrome, Sjogren's syndrome,chronic sinusitis, cholestatic jaundice, emphysema, idiopathic chronicpancreatitis, isolated obstructive azoospermia, sclerosing cholangitis,panbronchiolite, neonatal hypertripsinemia, adrenoleukodystrophy,Stargardt disease, Tangier disease, progressive familial intrahepaticcholestasis, Dubin-Johnson syndrome, elastic pseudoxantoma, persistenthyperinsulinemic hypoglycemia of infancy due to focal adenomatoushyperplasia, senile macular degeneration, retinitis pigmentosa and“cone-rod” retinal dystrophy; preferably said smoking-related lungpathology is chronic obstructive pulmonary disease.
 17. The methodaccording to claim 1, wherein said pathology is cystic fibrosis.
 18. Themethod according to claim 1, wherein the CFTR (Cystic FibrosisTransmembrane conductance Regulator) protein bears the F508del mutationand/or the G542X premature stop codon mutation.
 19. (canceled) 20.(canceled)
 21. (canceled)
 22. (canceled)
 23. (canceled)
 24. (canceled)25. (canceled)
 26. (canceled)
 27. A compound of general formula (I):

wherein: A is a pentatomic or hexatomic aromatic heterocyclic ring,comprising one, two or three heteroatoms selected from nitrogen, oxygenand sulfur; R is selected from the group consisting of: hydrogen, linearor branched C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, arylsulfonyl, halogen and alkylamine,wherein said linear or branched C1-C6 alkyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, arylsulfonyl oralkylamine is optionally substituted with one or more substituentsindependently selected from: linear or branched C1-C6 alkyl, nitro,amino, halogen, haloalkyl and alkoxy; R¹ and R² are independentlyselected from the group consisting of: hydrogen, carboxylic acid,carboxylic ester, carboxamide from primary, secondary or tertiary amine,halogen, nitro, amine, azide, alkylamine, arylalkyl and trifluoroalkyl,wherein said carboxylic acid, carboxylic ester, carboxamide fromprimary, secondary or tertiary amine, halogen, nitro, amine, azide,alkylamine or trifluorolalkyl is optionally substituted with one or moresubstituents independently selected from: linear or branched C1-C6alkyl, cycloalkyl, nitro, amino, halogen, arylsulfonyl, optionallysubstituted heteroaryl and haloalkyl; R³ is absent or present and isselected from the group consisting of: carbonitrile, carboxylic ester,carboxamide, alkylsulfonyl, arylsulfonyl, wherein said carboxylic ester,carboxamide, alkylsulfonyl or arylsulfonyl is optionally substitutedwith one or more substituents independently selected selected from:linear or branched C1-C6 alkyl, nitro, amino, halogen and haloalkyl; Bis a cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring, wherein saidheterocycloalkyl or heteroaryl ring comprises at least one heteroatomselected from nitrogen, oxygen and sulfur; R⁴ is selected from the groupconsisting of: hydrogen, alkyl, aryl, arylalkyl and heteroaryl; X isselected from the group consisting of: C═O, C—O-alkyl, andC—NR^(a)R^(b); R^(a) and R^(b) are independently selected from the groupconsisting of: hydrogen, alkyl, cycloalkane, aryl, arylalkyl,heteroaryl, heteroarylalkyl, acetyl, arylsulfonyl; wherein said alkyl,cycloalkane, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acetyl orarylsulfonyl is optionally substituted with one or more substituentsindependently selected from: C1-C6 alkyl, nitro, amino, halogen andhaloalkyl; Y is absent or present and is selected from the groupconsisting of: hydrogen, alkyl, aryl and alkylamine; wherein when X isC—O-alkyl or C—NR^(a)R^(b), Y is absent; Q is a carbon or nitrogen atom,wherein when Q is a nitrogen atom, R³ is absent; n is 0, 1, 2 or 3; m is1 or 2; or a pharmaceutically acceptable salt, tautomer, stereoisomer,deuterated derivative, active metabolite thereof.
 28. The compound orthe pharmaceutically acceptable salt, tautomer, stereoisomer, deuteratedderivative, active metabolite thereof according to claim 27, whereinwhen X is C═O, R² is different from hydrogen.
 29. The compound or thepharmaceutically acceptable salt, tautomer, stereoisomer, deuteratedderivative, active metabolite thereof according to claim 27, wherein R⁴is hydrogen.
 30. The compound or the pharmaceutically acceptable salt,tautomer, stereoisomer, deuterated derivative, active metabolite thereofaccording to claim 27, wherein m is
 1. 31. The compound or thepharmaceutically acceptable salt, tautomer, stereoisomer, deuteratedderivative, active metabolite thereof according to claim 27, wherein Bis a cycloalkyl or aryl ring, preferably B is cyclohexyl, cycloheptyl orphenyl.
 32. The compound or the pharmaceutically acceptable salt,tautomer, stereoisomer, deuterated derivative, active metabolite thereofaccording to claim 27, wherein n is 1 or
 2. 33. The compound or thepharmaceutically acceptable salt, tautomer, stereoisomer, deuteratedderivative, active metabolite thereof according to claim 27, wherein Ais a pentatomic aromatic heterocyclic ring comprising one or twonitrogen atoms, preferably A is selected from the group consisting of:


34. The compound or the pharmaceutically acceptable salt, tautomer,stereoisomer, deuterated derivative, active metabolite thereof accordingto claim 27, wherein X is C═O, C—OMe, C—NH₂ or C—NHR^(a).
 35. Thecompound or the pharmaceutically acceptable salt, tautomer,stereoisomer, deuterated derivative, active metabolite thereof accordingto claim 27, wherein: Q is a carbon atom, X is C═O and Y is hydrogen oralkyl, or Q is a carbon atom, X is C—Oalkyl and Y is absent, or Q is anitrogen atom, X is C—NR^(a)R^(b) and Y is absent.
 36. The compound orthe pharmaceutically acceptable salt, tautomer, stereoisomer, deuteratedderivative, active metabolite thereof according to claim 27 having oneof the following general formulas:


37. The compound or the pharmaceutically acceptable salt, tautomer,stereoisomer, deuterated derivative, active metabolite thereof accordingto claim 27, wherein R¹ and/or R² is a carboxylic ester or a carboxamidefrom primary, secondary or tertiary amine.
 38. The compound or thepharmaceutically acceptable salt, tautomer, stereoisomer, deuteratedderivative, active metabolite thereof according to claim 27, wherein R²is halogen.
 39. The compound or the pharmaceutically acceptable salt,tautomer, stereoisomer, deuterated derivative, active metabolite thereofaccording to claim 27, wherein R³ is arylsulfonyl or R³ is absent, Q isa nitrogen atom, X is C—NR^(a)R^(b), R^(a) is H and R^(b) isarylsulfonyl.
 40. The compound or the pharmaceutically acceptable salt,tautomer, stereoisomer, deuterated derivative, active metabolite thereofaccording to claim 27 selected from the group consisting of: Ethyl1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP015); Ethyl1-(3-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP016); Ethyl1-(4-chlorobenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP017); Ethyl7-[(4-chlorophenyl)sulfonyl]-1-(4-methylbenzyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP018); Ethyl7-(benzenesulfonyl)-1-[(2,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP021); Ethyl7-(benzenesulfonyl)-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP025); Propan-2-yl7-(benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP022); Ethyl7-(4-methylbenzene-1-sulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP023); Ethyl7-(metansulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP024); Methyl1-(4-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP019); Methyl1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP020); Ethyl8-(benzenesulfonyl)-1-[(4-methylphenyl)methyl]-9-oxo-1,4,5,6,9,10-hexahydropyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridine-2-carboxylate(PP048); Ethyl7-(benzenesulfonyl)-1-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP060); Ethyl7-(benzenesulfonyl)-1-[(4-iodophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP062); Ethyl7-(benzenesulfonyl)-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP064); Ethyl7-(benzenesulfonyl)-1-[(6-methylpyridin-3-yl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP066); Ethyl7-(benzenesulfonyl)-8-oxo-1-[(2,4,6-trimethylphenyl)methyl]-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP068); Ethyl7-(benzenesulfonyl)-8-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP070); Ethyl7-(benzenesulfonyl)-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP072); Ethyl7-(benzenesulfonyl)-1-[3-(dimethylamino)propyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP074); Propan-2-yl7-(benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP103); Propan-2-yl7-(benzenesulfonyl)-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP105); Propan-2-yl7-(benzenesulfonyl)-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP107);7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP083);7-(Benzenesulfonyl)-N-cyclopropyl-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP084);7-(Benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP085);7-(Benzenesulfonyl)-N-cyclopropyl-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP087);7-(Benzenesulfonyl)-1-[(4-bromophenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP096);7-(Benzenesulfonyl)-1-[(4-bromophenyl)methyl]-N-cyclopropyl-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP098); Ethyl7-(benzenesulfonyl)-3-chloro-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP076); Ethyl7-(benzenesulfonyl)-3-iodo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP077); allowing the isolation of N-methyl derivatives and O-methylderivatives as pure products. Ethyl7-(benzenesulfonyl)-8-methoxy-1-[(4-methylphenyl)methyl]-4,5-dihydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP014); Ethyl8-(benzenesulfonyl)-9-methoxy-1-[(4-methylphenyl)methyl]-1,4,5,6-tetrahydropyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridine-2-carboxylate(PP055); Ethyl7-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP008); Ethyl8-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-9-oxo-1,4,5,6,9,10-hexahydropyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridine-2-carboxylate(PP056); Ethyl 3-bromo1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP027); Ethyl 3-bromo1-(3-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP028); Ethyl 3-bromo1-(4-chlorobenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP029); Methyl3-bromo-1-(4-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP031); Methyl3-bromo-1-(2-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP032); Ethyl3-bromo-7-[(4-chlorophenyl)sulfonyl]-1-(3-methylbenzyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP030); Ethyl7-(benzenesulfonyl)-3-bromo-1-[(2,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP033); Ethyl7-(benzenesulfonyl)-3-bromo-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP037); Propan-2-yl7-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP034); Ethyl3-bromo-7-(4-methylbenzene-1-sulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP035); Ethyl3-bromo-7-(metansulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP036); Ethyl7-(benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-8,9-dihydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(14, PP057); Ethyl7-(benzenesulfonyl)-3-bromo-1-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP061); Ethyl7-(benzenesulfonyl)-3-bromo-1-[(4-iodophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP063); Ethyl7-(benzenesulfonyl)-3-bromo-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP065); Ethyl7-(benzenesulfonyl)-3-bromo-1-[(6-methylpyridin-3-yl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP067); Ethyl7-(benzenesulfonyl)-3-bromo-8-oxo-1-[(2,4,6-trimethylphenyl)methyl]-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP069); Ethyl7-(benzenesulfonyl)-3-bromo-8-oxo-1-{[4-(trifluoromethyl)phenyl]methyl}-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP071); Ethyl7-(benzenesulfonyl)-3-bromo-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP073); Ethyl7-(benzenesulfonyl)-1-[3-(dimethylamino)propyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP075); Propan-2-yl7-(benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP104); Propan-2-yl7-(benzenesulfonyl)-3-bromo-1-(cyclopropylmethyl)-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP106); Propan-2-yl7-(benzenesulfonyl)-3-bromo-1-[(4-fluorophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(PP108);7-(Benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP091);7-(Benzenesulfonyl)-N-cyclopropyl-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP092);7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP086);7-(Benzenesulfonyl)-3-bromo-N-cyclopropyl-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP088);7-(Benzenesulfonyl)-3-bromo-1-[(4-bromophenyl)methyl]-8-oxo-N-(propan-2-yl)-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP097);7-(Benzenesulfonyl)-3-bromo-1-[(4-bromophenyl)methyl]-N-cyclopropyl-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP099);7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP090);7-(Benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP081);7-(Benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP078);7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP079);7-(Benzenesulfonyl)-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP094);7-(Benzenesulfonyl)-3-bromo-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylicacid (PP095);7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP093);7-(Benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP082);7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP080);7-(Benzenesulfonyl)-3-bromo-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP089);N,7-di(benzenesulfonyl)-3-bromo-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP100);7-(Benzenesulfonyl)-3-bromo-N-tert-butyl-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP101);7-(Benzenesulfonyl)-3-bromo-N-(5-tert-butyl-1,2-oxazol-3-yl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrrolo[3,2-h]quinoline-2-carboxamide(PP102); Ethyl1-(4-methylbenzyl)-8-oxo-7-(phenylsulfonyl)-8,9-dihydro-1H-pyrrolo[3,2-h]quinoline-2-carboxylate(13, PP058); Ethyl2-amino-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ1); Ethyl2-amino-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ3); Ethyl2-amino-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ5); Ethyl2-amino-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ7); Ethyl2-[(benzenesulfonyl)amino]-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ9); Ethyl2-[(benzenesulfonyl)amino]-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ11); Ethyl2-[(benzenesulfonyl)amino]-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ13); Ethyl2-[(benzenesulfonyl)amino]-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ15); Ethyl2-amino-7-bromo-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ2); Ethyl2-amino-7-bromo-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ4); Ethyl2-amino-7-bromo-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ6); Ethyl2-amino-7-bromo-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ8); Ethyl2-[(benzenesulfonyl)amino]-7-bromo-9-[(4-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ10); Ethyl2-[(benzenesulfonyl)amino]-7-bromo-9-[(3-methylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ12); Ethyl2-[(benzenesulfonyl)amino]-7-bromo-9-[(3,4-dimethylphenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ14); Ethyl2-[(benzenesulfonyl)amino]-7-bromo-9-[(4-bromophenyl)methyl]-6,9-dihydro-5H-pyrrolo[3,2-h]quinazoline-8-carboxylate(SVQ16); Ethyl3-(benzenesulfonyl)-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN1); Ethyl3-(benzenesulfonyl)-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN5); Propan-2-yl3-(benzenesulfonyl)-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN9); Propan-2-yl3-(benzenesulfonyl)-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN13); Ethyl3-(benzenesulfonyl)-2-methoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN3); Ethyl3-(benzenesulfonyl)-1-methyl-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN4); Ethyl3-(benzenesulfonyl)-2-methoxy-6,7-dihydro-5H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN7); Ethyl3-(benzenesulfonyl)-1-methyl-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN8); Propan-2-yl3-(benzenesulfonyl)-2-methoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN11); Propan-2-yl3-(benzenesulfonyl)-1-methyl-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN12); Propan-2-yl3-(benzenesulfonyl)-2-methoxy-6,7-dihydro-5H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN15); Propan-2-yl3-(benzenesulfonyl)-1-methyl-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN16); Ethyl3-(benzenesulfonyl)-9-bromo-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN2); Ethyl3-(benzenesulfonyl)-10-bromo-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN6); Propan-2-yl3-(benzenesulfonyl)-9-bromo-2-oxo-1,2,5,6-tetrahydropyrrolo[1,2-h][1,7]naphthyridine-8-carboxylate(QZN10); Propan-2-yl3-(benzenesulfonyl)-10-bromo-2-oxo-1,5,6,7-tetrahydro-2H-pyrido[2,3-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZN14); Ethyl2-amino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate (QZQ1); Ethyl2-amino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ5); Propan-2-yl2-amino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate (QZQ17);Propan-2-yl2-amino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ21); Ethyl2-anilino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate (QZQ2);Ethyl2-(cyclohexylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ3); Ethyl2-anilino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ6); Ethyl2-(cyclohexylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ7); Propan-2-yl2-anilino-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate (QZQ18);Propan-2-yl2-(cyclohexylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ19); Propan-2-yl2-anilino-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ22); Propan-2-yl2-(cyclohexylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ23); Ethyl2-(cyclopentylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ14); Ethyl2-(cyclopentylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ15); Propan-2-yl2-(cyclopentylamino)-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate(QZQ20); Propan-2-yl2-(cyclopentylamino)-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ24); Ethyl2-acetamido-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate (QZQ4);Ethyl2-acetamido-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ8); Propan-2-yl2-acetamido-5,6-dihydropyrimido[5,4-g]indolizine-8-carboxylate (QZQ25);Propan-2-yl2-acetamido-6,7-dihydro-5H-pyrimido[4,5-c]pyrrolo[1,2-a]azepine-9-carboxylate(QZQ26); Ethyl7-(benzenesulfonyl)-1-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ1); Ethyl7-(benzenesulfonyl)-2-[(4-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ2); Ethyl7-(benzenesulfonyl)-1-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ3); Ethyl7-(benzenesulfonyl)-2-[(3-methylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ4); Ethyl7-(benzenesulfonyl)-1-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ5); Ethyl7-(benzenesulfonyl)-2-[(4-bromophenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ6); Ethyl7-(benzenesulfonyl)-1-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ7); Ethyl7-(benzenesulfonyl)-2-[(3,4-dimethylphenyl)methyl]-8-oxo-4,5,8,9-tetrahydro-2H-pyrazolo[4,3-h]quinoline-3-carboxylate(PZ8).
 41. (canceled)
 42. (canceled)
 43. A method for the treatmentand/or prevention of a pathology associated with a defect in an ABC(ATP-binding cassette) transporter and/or for the treatment and/orprevention of a pathology associated with at least one of the following:protein mutation, protein misfolding, protein degradation, proteinmaturation, protein trafficking, comprising administering a compound ofclaim 27 to a patient in need thereof.